Tachykinin receptor antagonists

ABSTRACT

The present invention relates to selective NK-1 receptor antagonists of Formula (I) or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins.

The present invention provides compounds of Formula (I), compositionsthereof, and a method of antagonizing the NK-1 subtype of tachykininreceptor that comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I). In addition, the presentinvention relates to processes for preparing the compounds of Formula Iand intermediates thereof.

Tachykinins are a family of peptides that are widely distributed in boththe central and peripheral nervous systems. These peptides exert anumber of biological effects through actions at tachykinin receptors. Todate, three such receptors have been characterized, including the NK-1,NK-2, and NK-3 subtypes of tachykinin receptor.

The role of the NK-1 receptor subtype in numerous disorders of thecentral nervous system and the periphery has been thoroughlydemonstrated in the art. For instance, NK-1 receptors are believed toplay a role in depression, anxiety, and central regulation of variousautonomic, as well as cardiovascular and respiratory functions. NK-1receptors in the spinal cord are believed to play a role in paintransmission, especially the pain associated with migraine andarthritis. In the periphery, NK-1 receptor activation has beenimplicated in numerous disorders, including various inflammatorydisorders, asthma, and disorders of the gastrointestinal andgenitourinary tract.

There is an increasingly wide recognition that selective NK-1 receptorantagonists would prove useful in the treatment of many diseases of thecentral nervous system and the periphery. While many of these disordersare being treated by new medicines, there are still many shortcomingsassociated with existing treatments. For example, the newest class ofanti-depressants, selective serotonin reuptake inhibitors (SSRIs), areincreasingly prescribed for the treatment of depression; however, SSRIshave numerous side effects, including nausea, insomnia, anxiety, andsexual dysfunction. This could significantly affect patient compliancerate. As another example, current treatments for chemotherapy-inducednausea and emesis, such as the 5-HT₃ receptor antagonists, areineffective in managing delayed emesis. The development of NK-1 receptorantagonists will therefore greatly enhance the ability to treat suchdisorders more effectively. Thus, the present invention provides a classof potent, non-peptide NK-1 receptor antagonists, compositionscomprising these compounds, and methods of using the compounds.

The present invention provides compounds of Formula (I):

wherein:

-   D¹ is a C₁-C₃ alkane-diyl;

-   D² is CH or nitrogen;

-   D⁴ is oxygen or sulfur;

-   R¹ is phenyl,    -   which phenyl is optionally substituted with one to three        substitutents independently selected from the group consisting        of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, difluoromethyl,        trifluoromethyl, and trifluoromethoxy;

-   R² is selected from the group consisting of hydroxy, C₁-C₄ alkyl,    optionally substituted phenyl, naphthyl, C₃-C₁₀ cycloalkyl, pyridyl,    optionally substituted pyrrolidinyl, optionally substituted    piperidinyl,    -   which C₁-C₄ alkyl is optionally substituted with hydroxy, C₁-C₂        alkoxy, optionally substituted phenyl, pyridyl, —NR⁶R⁷, or        naphthyl;        -   which pyridyl is further optionally substituted with one to            two halo, C₁-C₃ alkyl;

-   

R³ is C₁-C₄ alkyl, optionally substituted phenyl, —C(O)—R⁴, or—S(O)₂—R⁴,

-   -   which C₁-C₄ alkyl is further optionally substituted with R⁴;    -   R⁴ is optionally substituted phenyl;

-   or R² and R³, together with the nitrogen to which they are attached,    form a 4-11 membered heterocyclic ring,

which heterocyclic ring is further optionally substituted with one tofour substituents independently selected from the group consisting ofoptionally substituted phenyl, C₃-C₆ cycloalkyl, pyridyl, halo, hydroxy,oxo, and C₁-C₄ alkyl;

-   -   -   wherein the C₁-C₄ alkyl is further optionally substituted            with one to two substituents selected from the group            consisting of C₁-C₃ alkoxy, optionally substituted phenyl,            oxo, phenoxy, pyridyl, and pyrrolidinyl;

-   R⁶ and R⁷ are each independently hydrogen, C₁-C₄ alkyl, —S(O)₂—CH₃,    or C₁-C₄ alkoxycarbonyl, or R⁶ and R⁷, together with the nitrogen to    which they are attached, form a 4-7 membered saturated heterocyclic    ring;

-   R⁵ is hydrogen, halo, trifluoromethyl, C₁-C₄ alkyl, C₁-C₄ alkoxy,    C₃-C₆ cycloalkyl, furyl, pyrazolyl, imidazolyl, —NR¹³R¹⁴,    pyridyloxy, benzyloxy, phenyl, phenoxy, pyrrolyl, thienyl,    phenylthio, or anilino,    -   which phenyl, phenoxy, pyrrolyl, thienyl, phenylthio, or anilino        group may be optionally substituted on the ring with one to two        substituents independently selected from the group consisting of        halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, and        —S(O)_(q)(C₁-C₄ alkyl),

-   or R⁵ is a radical selected from the group consisting of:    wherein

-   W is a bond, —CHR¹⁵—, —C(O)—, —O—, —NR¹⁵—, or —S(O)_(q)—;    -   q is 0, 1, or 2;    -   R¹⁵ is selected from the group consisting of hydrogen, hydroxy,        C₁-C₄ alkyl, acetyl, carbamoyl, phenyl, benzyl, and —S(O)₂CH₃;

-   Z¹, Z², and Z³ are each independently CH or nitrogen;

-   R¹³ and R¹⁴ are each independently hydrogen, C₁-C₄ alkyl, —S(O)₂—CH₃    or C₃-C₆ cycloalkyl;    -   wherein the C₁-C₄ alkyl is optionally substituted with one C₁-C₂        alkoxy or di(C₁-C₂ alkyl)amino;

-   or R¹³ and R¹⁴, together with the nitrogen to which they are    attached, form a 4-7 membered saturated heterocyclic ring;    -   which 4-7 membered saturated heterocyclic ring is further        optionally substituted with one to two C₁-C₂ alkyl;

-   or a pharmaceutically acceptable salt thereof;

-   with the proviso that the following compounds are not claimed:

-   [5-methyl-1-(3-pyrrolidin-1-ylpropyl)-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;    {1-[2-(4-nitrophenyl)ethyl]-5-methyl-1H-1,2,3-triazol-4-yl    }piperazin-1-yl-methanone;    [1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;    [5-methyl-1-(3-imidazol-1-ylpropyl)-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;    (5-methyl-1-benzyl-1H- 1,2,3-triazol-4-yl)piperazin-1-yl-methanone;    (1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1,4-diazepan-1-yl-methanone;

-   [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-morpholin-4-yl-methanone;    1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylic    acid (2-amino-ethyl)-(2-chloro-benzyl)-amide dihydrochloride;    1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic    acid (2-amino-ethyl)-(2-chloro-benzyl)-amide hydrochloride;    1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic    acid (2-amino-ethyl)-[1-(2-chlorophenyl)-ethyl)-amide    dihydrochloride;    1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridyl-4-yl-1H-[1,2,3]triazole-4-carboxylic    acid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide    dihydrochloride;

-   {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl}-carbamic    acid tert-butyl ester;    {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl}-carbamic    acid tert-butyl ester;    (2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamic    acid tert-butyl ester;    (2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamic    acid tert-butyl ester;    {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl}-carbamic    acid tert-butyl ester; and    (2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl    -1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamic    acid tert-butyl ester.

The compounds of Formula I are antagonists of tachykinin receptors.Specifically, the compounds of Formula I are antagonists of the NK-1subtype of tachykinin receptor. Because these compounds inhibit thephysiological effects associated with an excess of tachykinins, thecompounds are useful in the treatment of numerous disorders related totachykinin receptor activation. These disorders include: anxiety,depression, psychosis, and schizophrenia and other psychotic disorders;neurodegenerative disorders such as dementia, including senile dementiaof the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia,and Down's syndrome; seizure disorders, such as epilepsy; demyelinatingdiseases such as multiple sclerosis and amyotrophic lateral sclerosisand other neuropathological disorders, such as peripheral neuropathy,diabetic and chemotherapy-induced neuropathy, and post-herpetic andother neuralgias; acute and chronic obstructive airway diseases such asadult respiratory distress syndrome, bronchopneumonia, bronchospasm,chronic bronchitis, drivercough, and asthma; inflammatory diseases suchas inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis,and rheumatoid arthritis; disorders of the musculo-skeletal system, suchas osteoporosis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like; cutaneous diseasessuch as contact dermatitis, atopic dermatitis, urticaria, and othereczematoid dermatites; addiction disorders such as alcoholism;stress-related somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancement or suppression such as systemic lupuserythematosis; gastrointestinal disorders or diseases associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease and irritable bowel syndrome; disorders of bladder function suchas bladder detrusor hyper-reflexia and incontinence; atherosclerosis;fibrosin and collagen diseases such as scleroderma and eosinophilicfascioliasis; irritative symptoms of benign prostatic hypertrophy;disorders associated with blood pressure, such as hypertension; ordisorders of blood flow caused by vasodilation and vasospastic diseases,such as angina, migraine, and Reynaud's disease; emesis, includingchemotherapy-induced nausea and emesis; and pain or nociception, forexample, that attributable to or associated with any of the foregoingconditions.

In one embodiment, this invention provides a pharmaceutical compositioncomprising, as an active ingredient, a compound of Formula I, or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers, diluents, or excipients.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Formula I, and intermediates thereof.

In another embodiment, the present invention provides a method ofselectively antagonizing an NK-1 receptor by contacting the receptorwith a compound of Formula I, or a pharmaceutically acceptable saltthereof.

In another embodiment, this invention provides methods of treating acondition associated with an excess of tachykinins, comprising:administering to a patient in need thereof an effective amount of acompound of Formula I, or a pharmaceutically acceptable salt thereof.That is, the present invention provides for the use of a compound ofFormula I, or a pharmaceutical composition thereof, for the treatment ofa disorder associated with an excess of tachykinins.

In another aspect, the present invention provides for the use of acompound of Formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for antagonizing the NK-1 receptor.Thus, the present invention provides for the use of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disorder associatedwith an excess of tachykinins by means of the method described above.

Of the disorders listed above, depression, anxiety, schizophrenia andother psychotic disorders, emesis, pain, asthma, inflammatory boweldisease, irritable bowel syndrome, and dermatitis are of importance. Ofthese disorders, depression and anxiety are of particular importance.

Thus, in a preferred embodiment, the present invention provides a methodfor treating major depressive disorder, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating generalized anxiety disorder, comprising: administering toa patient in need thereof an effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating panic disorder, comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating obsessive compulsive disorder, comprising: administering toa patient in need thereof an effective amount of a compound of FormulaI, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating social phobia, comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating irritable bowel syndrome, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating inflammatory bowel disease, comprising: administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the present invention provides a methodfor treating emesis (including chemotherapy-induced nausea and acute ordelayed emesis), comprising: administering to a patient in need thereofan effective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof.

The terms and abbreviations used in the preparations and examples havetheir normal meanings unless otherwise designated. For example “° C.”refers to degrees Celsius; “N” refers to normal or normality; “mol”refers to mole or moles; “mmol” refers to millimole or millimoles; “h”refers to hour(s); “eq” refers to equivalent; “g” refers to gram orgrams; “L” refers to liter or liters; “mL” refers to millilitermilliliters; “M” refers to molar or molarity; “brine” refers to asaturated aqueous sodium chloride solution; “J” is an NMR couplingconstant, reported in hertz; “ES” refers to electrospray; “MS” refers tomass spectrometry; “NMR” refers to nuclear magnetic resonancespectroscopy; “TLC” refers to thin layer chromatography; “ACN” refers toacetonitrile; “DMF” refers to N,N-dimethylformamide; “DMSO” refers todimethylsulfoxide; “Et₂O” refers to diethyl ether; “EtOAc” refers toethyl acetate; “MeOH” refers to methanol; “EtOH” refers to ethanol;“iPrOH” refers to isopropanol; “TEA” refers to triethylamine; “TFA”refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “HOAt”refers to 1-hydroxy-7-azabenzotriazole; and “HOBt” refers to1-hydroxy-benzotriazole; “DAST” refers to (Diethylamino)sulfurtrifluoride.

As used herein, the term “C₁-C₄ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 4 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. The terms “C₁-C₃ alkyl” and“C₁-C₂ alkyl” are encompassed within the definition of “C₁-C₄ alkyl.”

The term “optionally substituted phenyl” refers to a phenyl that isunsubstituted or substituted with one to three substituentsindependently selected from the group consisting of halo, hydroxy, C₁-C₄alkyl, C₁-C₄ alkoxy, trifluoromethyl, triflouromethoxy, and—NR^(x)R^(y), wherein R^(x) is H or C₁-C₄ alkyl, and R^(y) is H, orC₁-C₄ alkyl; or R^(x) and R^(y), together with the N to which they areattached, form a 4-7 membered saturated heterocyclic ring.

Examples of “4-7 membered saturated heterocyclic rings” include, but arenot limited to, azetidinyl, pyrrolidinyl, piperidinyl (piperidyl orpiperidino), hexamethyleneiminyl (homopiperidinyl), piperazinyl, andmorpholin-4-yl (morpholino).

The term “optionally substituted pyrrolidinyl” refers to apyrrolidin-1-yl, pyrrolidin-2-yl, or pyrrolidin-3-yl that isunsubstituted or substituted with one substituent selected from C₁-C₃alkyl, phenyl, or benzyl.

The term “optionally substituted piperidinyl” refers to a piperidin-1-yl(piperidino), piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl that isunsubstituted or substituted with one substituent selected from C₁-C₃alkyl, phenyl, or benzyl.

When R² and R³, together with the nitrogen to which they are attached,form a “4-11 membered heterocyclic ring,” such 4-11 memberedheterocyclic rings include saturated or unsaturated monocyclicheterocyclic rings containing nitrogen, and optionally containing oneadditional heteroatom selected from nitrogen, oxygen, or sulfur, andfurther include a bicyclic ring in which any of the above-definedmonocyclic heterocyclic rings is fused to a benzene ring. Examples ofsuch 4-11 membered heterocyclic rings include, but are not limited to,pyrrolidinyl, pyrrolyl, diazolidinyl, oxazolidinyl, pyrazolidinyl,thiazolidinyl, piperidino, piperazinyl, hexahydropyridazinyl, indolinyl,benzazepanyl, tetrahydroisoquinolinyl, and tetrahydroquinolinyl.

“C₁-C₃ alkane-diyl” refers to a straight or branched, divalent,saturated aliphatic chain of 1 to 3 carbon atoms and includes, but isnot limited to, methylene, ethylene, ethane-1,1-diyl, propane-1,1-diyl,propane-1,2-diyl, propane-1,3-diyl, and propane-2,2-diyl. The term“C₁-C₂ alkane-diyl” is encompassed within the definition of “C₁-C₃alkane-diyl.”

“C₁-C₄ alkoxy” represents a C₁-C₄ alkyl group, as defined above, linkedto the parent molecule through an oxygen atom. Typical C₁-C₄ alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, and the like. The term “C₁-C₄ alkoxy” includes within itsdefinition the term “C₁-C₃ alkoxy” and “C₁-C₂ alkoxy.”

“C₃-C₁₀ cycloalkyl” represents a saturated monocyclic hydrocarbon ringstructure containing from three to six carbon atoms (C₃-C₆ cycloalkyl),and further represents a bicyclic ring in which the above-defined C₃-C₆cycloalkyl is fused to a benzene ring. Typical C₃-C₁₀ cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl,tetrahydronaphthyl, and the like.

“Halo,” “halogen,” and “halide” represent a chloro, fluoro, bromo oriodo atom. Preferred halogens include chloro and fluoro.

“C₁-C₄ alkoxycarbonyl” represents a straight or branched C₁-C₄ alkoxychain, as defined above, that is attached via the oxygen atom of thealkoxy to a carbonyl moiety. Typical C₁-C₄ alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl and the like.

The term “Pg” refers to an alcohol, carboxyl, or amino protecting group.Typical protecting groups include tetrahydropyranyl (THP), silanes suchas trimethylsilane (TMS), tert-butyldimethylsilyl (TBDMS), andtert-butyldiphenylsilane (TBDPS), methoxymethyl (MOM), benzyl (Bn),p-methoxybenzyl, formyl, acetyl (Ac), and tert-butoxycarbonyl (t-BOC).Typical carboxyl protecting groups may include methyl, ethyl, andtert-butyl. The selection and use of protecting groups is well known andappreciated in the art. See for example, Protecting Groups in OrganicSynthesis, Theodora Greene (Wiley-Interscience); Protecting Groups,Philip J. Kocienski, Thieme Medical Publishers, inc: New York 1994,chapters 2,4,6.

It is understood that when any substituent is a pyridyl radical, theradical may be a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. When asubstituent is furyl or thienyl, the radical may be attached at the 2-,or 3-position of the radical. When a substituent is pyrrolyl orimidazolyl, the radical may be attached at the 1-, 2-, or 3 position ofthe pyrrolyl, or the 1, 2, or 4 position of the imidazolyl.

The compounds of the present invention may exist as stereoisomers. TheCahn-Prelog-Ingold designations of (R)- and (S)- and the designations ofL- and D- for stereochemistry relative to the isomers of glyceraldehydeare used herein to refer to specific isomers. The specific stereoisomerscan be prepared by stereospecific synthesis or can be resolved andrecovered by techniques known in the art, such as chromatography onchiral stationary phases, and fractional recrystallization of additionsalts formed by reagents used for that purpose. Useful methods ofresolving and recovering specific stereoisomers are known in the art anddescribed in E. L. Eliel and S. H. Wilen, Stereochemistry of OrganicCompounds, (Wiley-Interscience 1994), and J. Jacques, A. Collet, and S.H. Wilen, Enantiomers, Racemates, and Resolutions, Wiley-Interscience1981). It is understood that the present invention contemplates allenantiomers and mixtures of enantiomers, including racemates.

The skilled artisan will recognize that compounds of the presentinvention may exist as tautomers. It is understood that tautomeric formsof the compounds of Formula (I) are also encompassed in the presentinvention.

This invention includes the pharmaceutically acceptable salts of thecompounds of Formula I. A compound of this invention can possess asufficiently basic functional group, which can react with any of anumber of inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “pharmaceutically-acceptable salt” as used herein, refers to asalt of a compound of the above Formula I. It should be recognized thatthe particular counterion forming a part of any salt of this inventionis usually not of a critical nature, so long as the salt as a whole ispharmacologically acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole.

The compounds of Formula I and the intermediates described herein formpharmaceutically-acceptable acid addition salts with a wide variety oforganic and inorganic acids and include the physiologically-acceptablesalts which are often used in pharmaceutical chemistry. Such salts arealso part of this invention. A pharmaceutically-acceptable acid additionsalt is formed from a pharmaceutically-acceptable acid, as is well knownin the art. Such salts include the pharmaceutically acceptable saltslisted in Journal of Pharmaceutical Science, 66, 2-19 (1977), which areknown to the skilled artisan. See also, The Handbook of PharmaceuticalSalts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth(ED.s), Verlag, Zurich (Switzerland) 2002.

Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric,metaphosphoric, pyrophosphoric, and the like. Salts derived from organicacids, such as aliphatic mono and dicarboxylic acids, phenyl substitutedalkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromaticacids, aliphatic and aromatic sulfonic acids, may also be used. Suchpharmaceutically acceptable salts thus include acetate, phenylacetate,trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate,phenylbutyrate, α-hydroxybutyrate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate,formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate,maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate,isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate,ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate,naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate,tartarate, and the like.

As used herein, the term “patient” refers to a mammal that is afflictedwith one or more disorders associated with excess tachykinins. Guineapigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans areexamples of mammals within the scope of the meaning of the term. It willbe understood that the most preferred patient is a human. It is alsounderstood that this invention relates specifically to the inhibition ofmammalian NK-1 receptors.

It is also recognized that one skilled in the art may affect thedisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with the disorderswith an effective amount of the compound of Formula I. Thus, the terms“treatment” and “treating” are intended to refer to all processeswherein there may be a slowing, interrupting, arresting, controlling, orstopping of the progression of the disorders described herein, and isintended to include prophylactic treatment of such disorders, but doesnot necessarily indicate a total elimination of all disorder symptoms.

As used herein, the term “effective amount” of a compound of Formula Irefers to an amount that is effective in treating the disordersdescribed herein.

As with any group of pharmaceutically active compounds, some groups arepreferred in their end use application. Preferred embodiments of thepresent invention are discussed below.

Preferred embodiments of 4-11 membered heterocyclic rings areillustrated below. As described above, each of the preferred 4-11membered heterocyclic rings depicted below may be further optionallysubstituted with one to four substituents independently selected fromthe group consisting of optionally substituted phenyl, C₃-C₆ cycloalkyl,pyridyl, halo, hydroxy, oxo, and C₁-C₄ alkyl, wherein the C₁-C₄ alkyl isfurther optionally substituted with one to two substituents selectedfrom the group consisting of C₁-C₃ alkoxy, optionally substitutedphenyl, oxo, phenoxy, pyridyl, and pyrrolidinyl.

Especially preferred embodiments of the compounds of Formula (I) aregiven below.:

-   -   (a) D¹ is methylene.    -   (b) D² is nitrogen.    -   (c) D⁴ is oxygen.    -   (d) R¹ is phenyl, which phenyl is optionally substituted with        one to three substitutents independently selected from the group        consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano,        difluoromethyl, trifluoromethyl, and trifluoromethoxy.    -   (e) R¹is 3,5-bis-trifluoromethyl-phenyl.    -   (f) R⁵ is a radical of Formula (ID).    -   (g) R⁵ is phenyl.    -   (h) R⁵ is pyridin-4-yl.    -   (i) R⁵ is pyridin-3-yl.    -   (j) R⁵ is a radical of Formula (IC).    -   (k) R⁵ is morpholino.    -   (l) R² is C₁-C₄ alkyl, which C₁-C₄ alkyl is optionally        substituted with hydroxy, C₁-C₂ alkoxy, optionally substituted        phenyl, pyridyl, —NR⁶R⁷, or naphthyl.    -   (m) R³ is C₁-C₄ alkyl, which C₁-C₄ alkyl is optionally        substituted with R⁴.    -   (n) R² is 2-chloro-benzyl.    -   (o) R³ is methyl.    -   (p) R² and R³, together with the nitrogen to which they are        attached, form a 4-11 membered saturated heterocyclic ring,        which heterocyclic ring is further optionally substituted with        one to four substituents independently selected from the group        consisting of optionally substituted phenyl, C₃-C₆ cycloalkyl,        pyridyl, halo, hydroxy, oxo, and C₁-C₄ alkyl, wherein the C₁-C₄        alkyl is further optionally substituted with one to two        substituents selected from the group consisting of C₁-C₃ alkoxy,        optionally substituted phenyl, oxo, phenoxy, pyridyl, and        pyrrolidinyl.    -   (q) R² and R³, together with the nitrogen to which they are        attached, form pyrrolidine, which pyrrolidine is further        optionally substituted with one to four substituents        independently selected from the group consisting of optionally        substituted phenyl, C₃-C₆ cycloalkyl, pyridyl, halo, hydroxy,        oxo, and C₁-C₄ alkyl, wherein the C₁-C₄ alkyl is further        optionally substituted with one to two substituents selected        from the group consisting of C₁-C₃ alkoxy, optionally        substituted phenyl, oxo, phenoxy, pyridyl, and pyrrolidinyl.    -   (r) R² and R³, together with the nitrogen to which they are        attached, form 2-(2-chloro-phenyl)-pyrrolidine.

Schemes

The compounds disclosed herein can be made according to the followingschemes. The schemes, preparations, and examples should in no way beunderstood to be limiting in any way as to how the compounds may bemade.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula (I). Thepresent invention contemplates all stereoisomers, enantiomers, andmixtures of enantiomers, including racemates and diastereomers. It ispreferred that the compounds of the invention containing chiral centersare single enantiomers.

As the following schemes, preparations, and examples demonstrate, manyof the compounds of the present invention are not only selective NK-1receptor antagonists, but are also useful intermediates for thepreparation of additional compounds of Formula (I). It will berecognized by one of skill in the art that the individual steps in thefollowing schemes may be varied to provide the compounds of Formula (I).The particular order of steps required to produce the compounds ofFormula (I) is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. Some substituents have been eliminated in the followingschemes for the sake of clarity and are not intended to limit theteaching of the schemes in any way. In the schemes below, it will beclear that compounds of Formula (8), (9), and (1 8) are encompassedwithin the scope of the compounds of Formula (I).

In Scheme I, step a, alkyl azides of Formula (2) can be prepared usingstandard synthetic methods. For example, see Scriven and Turnbull, Chem.Rev. (1988) 88(2): 351-368.

In the compounds of Formula (1), X may be either a hydroxyl or a leavinggroup. Suitable leaving groups include halogen, tosylate, mesylate,nosylate, or triflate. Compounds of Formula (1) are readily available orcan be readily prepared.

When X of Formula (1) is a hydroxyl group, the alcohol of Formula (1) ismixed with an organic base, typically at approximately 8-12 molarequivalents of organic base per molar equivalent of the alcohol.Suitable organic bases may include triethylamine, diisopropylethylamine,pyridine, collidine, lutadine, or 1,8-diazabicyclo[5,4.0]undec-7-ene,with pyridine being the preferred base. A suitable sulfonylating agent,such as p-toluenesulfonyl chloride, methanesufonyl chloride,p-nitrobenzenesulfonyl chloride, or trifluoromethanesulfonic anhydride,preferably p-toluenesulfonyl chloride, is added in the reaction of stepa for the conversion of the hydroxy group of Formula (1) into a suitableleaving group. Typically, the sulfonylating agent is used in slightmolar excess to the alcohol of Formula (1).

Azide sources such as NaN₃, LiN₃, or tetrabutylammonium azide (Bu₄NN₃)are acceptable, with NaN₃ being preferred. Typically, about 1-3 molarequivalents of the azide source are used. The reaction of step a istypically carried out in a solvent, such as DMSO/H₂O,N,N-dimethylformamide, tetrahydrofuran, ethanol, methanol, and dioxane,preferably DMSO/H₂O, at temperatures ranging from room temperature toabout 80° C. In most cases, the resulting crude azide of Formula (2) canbe used without further purification.

When D¹ is methylene, compounds of Formula (1) in which X is a hydroxylgroup can be directly converted to the azide. Such reactions are wellknown and appreciated in the art. For example, see Thompson et al., J.Org. Chem. (1993) 58: 5886-5888. In such reactions, the alcohol ofFormula (1) is dissolved in a suitable solvent, such as toluene,benzene, tetrahydrofuran, or dioxane, with the preferred solvent beingtoluene, and the reaction of step a is carried out using adiphenylphosphoryl azide, followed by a suitable organic base, asdescribed above, with the preferred base being1,8-diazabicyclo[5,4.0]undec-7-ene. Typically about 1-3 molarequivalents of the azide source are used. The product of Formula (2) canbe isolated and purified by techniques well known in the art, such asprecipitation, filtration, extraction, evaporation trituration,chromatography, and recrystallization.

In the reaction of step b, shown in Scheme II, an alkyne of Formula (3)is dissolved in a suitable solvent, typically dichloromethane,chloroform, tetrahydrofuran, dioxane, or diethyl ether, and furtherreacted with a suitable base, such as lithium diisopropylamide,potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide,sodium bis(trimethylsilyl)amide, C₁-C₆ alkylmagnesium bromide,phenylmagnesium bromide, or n-butyllithium, with n-butyllithium beingthe preferred base. The reaction is carried out with an appropriatechloroformate agent, such as a C₁-C₆ alkyl (e.g., methyl, ethyl, propyl,butyl), aryl (e.g., phenyl), or benzyl chloroformate. Thus, Z is definedin compounds of Formula (4) as C₁-C₆ alkyl, aryl, or benzyl. Generally,the reaction proceeds at temperatures from about −78° C. to ambienttemperature. The product of Formula (4) can be isolated and purified bytechniques well known in the art, as described above.

In step c, hydrolysis of an alkynyl ester of Formula (4) to give acompound of Formula (5) is well known and appreciated in the art(Larock, R. C., Comprehensive Organic Transformations, 2^(nd) Ed.,copyright 1999, John Wiley & Sons, pp 1959-1968). For example, anappropriate ester of Formula (4) is dissolved in a suitable solvent,such as methanol, and is further treated with a suitable base, such assodium hydroxide, to give a compound of Formula (5).

The reaction of step d, in which a carboxylic acid, such as that ofFormula (5), is coupled with an appropriate amine, such as that ofFormula (6), under standard peptide coupling conditions, is well knownto the skilled artisan. Specifically, the amine and the carboxylic acidare coupled in the presence of a peptide coupling reagent, optionally inthe presence of a catalyst. Suitable peptide coupling reagents includeN,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), and1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (PEPC). Suitablecatalysts for the coupling reaction includeN,N-[dimethyl]-4-aminopyridine (DMAP). All of the reagents are combinedin a suitable solvent, typically dichloromethane, chloroform,tetrahydrofuran, dioxane, or diethyl ether, and are stirred for 1 to 72hours at temperatures ranging from ambient temperature to approximatelythe reflux temperature of the solvent. The desired product may beisolated and purified by techniques described above. Such couplingreactions are well known and appreciated in the art (Larock, R. C.,Comprehensive Organic Transformations, 2^(nd) Ed., copyright 1999, JohnWiley & Sons, pp 1941-1949).

Alternatively, a compound of Formula (5) may be converted to an acidchloride, preferably by reaction with oxalyl chloride, and used toacylate the appropriate amine of Formula (6) to give a compound ofFormula (7). Such acylation reactions are well known and appreciated inthe art (Larock, R. C., Comprehensive Organic Transformations, 2^(nd)Ed., copyright 1999, John Wiley & Sons, pp 1929-1930). The product canbe isolated and purified by techniques described above.

In reaction step e, a compound of Formula (2) is reacted with a compoundof Formula (7) to give a compound of Formula (8). The reaction isgenerally carried out in a suitable solvent, such as toluene, benzene,xylene, ethanol, N,N-dimethylformamide, dimethylsufoxide, ortetrahydrofuran, preferably toluene, typically at temperatures rangingfrom 60-120° C. The product can be isolated and purified by techniquesdescribed above.

In the optional reaction of step f, a compound of Formula (8) can betransformed to a thiocarbonyl compound of Formula (9) by[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](Lawesson'sReagent) or phosphorus pentasulfide, typically in a suitable solvent,for example, toluene, ethylene glycol dimethyl ether, benzene, pyridine,xylene, or tetrahydrofuran, preferably toluene. The reaction isgenerally carried out at temperatures of about room temperature to 100°C. The product can be isolated and purified by techniques describedabove.

As one of the variations mentioned above, shown in Scheme III, acompound of Formula (4) is cyclized with an azide of Formula (2), asdescribed in step e, to give the ester corresponding to the compound ofFormula (11), wherein D² is nitrogen. Subsequent hydrolysis, as taughtin step c, followed by amide formation, as taught in step d, gives thedesired compound of Formula (8). In the compounds depicted in SchemeIII, Z is C₁-C₆ alkyl, aryl, or benzyl.

Another variation for making compounds of Formula (I) is depicted instep g. In step g, the triazole ring of Formula (11), in which D² isnitrogen, is made by reacting a beta keto ester compound of Formula(10), such as a beta keto C₁-C₆ alkyl or benzyl ester, with an azide ofFormula (2). Such ring formations are well known and appreciated in theart. See Savini et al., Farmaco (1994) 49(5): 363-370; Martini et al.,J. Pharm. Sci. (1988) 77(11): 977-980; Sun et al., Magn. Reson. Chem.(1998) 36(6): 459-460; Settimo et al., Farmaco Ed. Sci. (1983) 38(10):725-737; Olesen et al., J. Heterocycl. Chem. (1984) 21: 1603-1608;L'abbe et al., Bull. Soc. Chim. Belg. (1987) 96(10): 823-824; Julino etal., J. Chem. Soc. Perkin Trans. I (1998) 10: 1677-1684; Mamedov et al.,Chem. Heterocycl. Compd. (Engl. Transl.) (1993) 29(5): 607-611; Wenderet al., Tetrahedron Lett. (1987) 28(49): 6125-6128; Freitas et al., J.Heterocycl. Chem. (1995) 32(2): 457-462; Cottrell et al., J. Heterocycl.Chem. (1991) 28(2): 301-304.

The reaction of step g is typically carried out in the presence of asuitable base, such as sodium carbonate, lithium carbonate, sodiumalkoxide (such as sodium methanolate or ethanolate), or potassiumalkoxide, (such as potassium methanolate or potassium ethanolate), orsodium hydride, with potassium carbonate being a preferred base.Generally, the reaction is carried out using 2-4 molar equivalents ofthe base in a suitable solvent, such as DMSO, methanol, ethanol, or DMF,with DMSO being a preferred solvent. The azide of Formula (2) and thebeta keto ester of Formula (4) are used at roughly molar equivalence.The reaction is carried out at temperatures of about 20-80° C., withreaction times ranging from approximately 4-24 hours. In general, basicconditions are favored for the condensation of the above compounds ofFormula (2). The product can be isolated and purified by techniquesdescribed above.

Compounds of Formula (11) in which D² is —CH may be made by the reactionof step h. A compound of Formula (13), in which Z can be C₁-C₆ alkyl,aryl, or benzyl, is prepared by methods described herein and by methodsdescribed in the art, for example, J. Org. Chem. (1994) 59: 7635. Anappropriate compound of Formula (13) can be condensed with anappropriate amine of Formula (14) to give the compound of Formula (11).Appropriate amines of Formula (14) are readily available. The reactionis typically carried out in the presence of a suitable organic base,such as triethylamine, diisopropylethylamine, pyridine, collidine,lutidine, or 1,8-diazabicyclo[5,4.0]undec-7-ene, preferablytriethylamine. The reaction is carried out in a suitable solvent, suchas 1-methyl-2-pyrrolidinone, DMF, toluene, tetrahydrofuran orchloroform, preferably DMF, at temperatures ranging from about 0 to 80°C. The product can be isolated and purified by standard techniques, asdescribed above.

Another variation for making compounds of Formula (I) is depicted inScheme IV, step i. In step i, the triazole ring of Formula (15), inwhich D² is nitrogen, is made by reacting a dialkylmalonate of Formula(14) with an azide of Formula (2). The hydroxyl group of the compound ofFormula (15) maybe readily converted to the corresponding halide, asshown in step j, to give a compound of Formula (16) wherein Y is ahalide. Examples of reagents for this reaction include PCl₅, POCl₃,PBr₃, POBr₃, and thionyl chloride, with PCl₅ as the preferred reagenteither neat or in a suitable solvent such as dichloromethane, benzene,or toluene at a temperature between 0 and 100° C. The preferred methodis reacting a compound of Formula (15) with PCl₅ in toluene at 40-60° C.This type of transformation is well known and appreciated in the art.See Buckle, D. R.; Rockell, C. J. M. J. Chem. Soc., Perkin I, 1982,627-630. Subsequent ester hydrolysis, as taught in step c, followed byamide formation, as taught in step d, gives compounds of Formula (18).As shown in step k, the halide of the compound of Formula (18) may besubstituted by reaction with an appropriate nucleophile such as, but notlimited to, primary amines, secondary amines, alcohols or thiols tofurther encompass compounds of the present invention to give the desiredcompounds of Formula (8). Such reactions are well known and appreciatedin the art. See March, J., Advanced Organic Chemistry, 1985, John Wileyand Sons, Inc., pp 255-446. In such reactions, the compound of Formula(18) is dissolved in a suitable solvent, such as DMF, THF, DMSO, andreacted with the appropriate nucleophile in the presence of a suitablebase. Such bases include triethylamine, potassium carbonate, cesiumcarbonate or sodium hydride. The reaction is generally carried out attemperatures ranging from room temperature to 100° C. In some cases, thereaction may be carried out neat, using the nucleophile as solvent. Theproduct of Formula (8) can be isolated and purified by techniquesdescribed above.

As depicted in Scheme II, a compound of Formula (8) can be transformedto a thiocarbonyl compound of Formula (9) by[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](Lawesson's Reagent) or phosphorus pentasulfide, typically in a suitablesolvent, for example, toluene, ethylene glycol dimethyl ether, benzene,pyridine, xylene, or tetrahydrofuran, preferably toluene. The reactionis generally carried out at temperatures of about room temperature to100° C. The product can be isolated and purified by techniques describedabove.

The skilled artisan will appreciate that the compounds of Formula (8),(9), and (18) in Schemes II, III, and IV may be formed into acidaddition salts using pharmaceutically acceptable acids. The formation ofacid-addition salts is well known and appreciated in the art.

Preparation 1 2-Amino-2-(2-chloro-phenyl)-acetamide hydrochloride

Stir a slurry of 2-chlorobenzaldehyde (43 mL, 380 mmol) and sodiumbisulfite (39.5 g) in water (150 mL) and MeOH (150 mL) for 15 min., thenadd ammonium hydroxide (26 mL, 380 mmol). Stir the mixture for 30 min.at RT, then cool to 0° C. Add MeOH (75 mL) to the mixture, then add asolution of sodium cyanide (18.6 g, 380 mmol) in water (75 mL) dropwiseover 15 min. Remove the ice bath and stir overnight. Evaporate off theorganics, then extract the aqueous layer with ether three times. Washthe combined ether extracts with water, and brine, dry over Na₂SO₄,filter, and concentrate to approximately 200 mL. Acidify the solution topH 4.5 with 2 N HCl. Cool the resulting slurry at 4° C. for 30 min.,then filter the precipitate and dry under vacuum to afford the titlecompound (2.1 g, 2.5%) as a white solid. MS(FD) 186.63 (M+). ¹H NMR (400MHz, DMSO-d₆) δ12.7 (br s, 1H), 7.33 (s, 1H), 7.22 (s, 2H), 5.07 (s,2H).

Preparation 2 [2-(2-Chloro-benzylamino)-ethyl]-carbamic acid tert-butylester

Dissolve 2-chlorobenzaldehyde (1.31 g, 9.3 mmol) andt-butyl-N-(2-aminoethyl) carbamate (1 g, 6.2 mmol) in dry MeOH (0.2M)and stir for one hour. Cool the solution to 0° C., and add NaBH₄ (2.81g, 74.4 mmol). After 15 min., warm the mixture to RT, and stir anotherhour. Quench with 1N NaOH (400 mL), extract with CH₂Cl₂ (2×250 mL), dryover Na₂SO₄, filter, and concentrate. Use without further purification.¹H NMR (CDCl₃, 250 MHz) δ7.40-7.22 (m, 4H), 3.90 (s, 2H), 3.25 (q, 2H,J=5.72 Hz), 2.79-2.74 (m, 2H), 1.47 (s, 9H); MS(ES) 285.1 (M+1)⁺.

Preparation 3 N¹-(2-Chloro-benzyl)-ethane-1,2-diamine

To a solution of [2-(2-chloro-benzylamino)-ethyl]-carbamic acidtert-butyl ester (450 mg, 1.76 mmol) in CH₂Cl₂ (0.2M), add anisole (571mg, 5.28 mmol) and trifluoroacetic acid (1.48 mL) and stir at RT. After12 h, dilute the solution with CH₂Cl₂ (15 mL) and extract with 1N HCl(15 mL). Make the aqueous layer basic with 5 N NaOH (10 mL) and extractwith CH₂Cl₂ (25mL), dry over Na₂SO₄, filter, and concentrate. Use crudematerial without further purification. ¹H NMR (CDCl₃, 250 MHz)δ7.19-7.40 (m, 4H), 3.89 (s, 2H), 2.83-2.85 (m, 2H), 2.68-2.71 (m, 2H);MS(ES) 185.1 (M+1)⁺.

Preparation 4 3-(2-Methyl-benzylamino)-propan-1-ol

Mix 1-bromomethyl-2-methyl-benzene (100 g, 0.5 mol) and3-amino-1-propanol (340 mL) and stir at RT. After 4 h, dilute themixture with H₂O (1 L), add 5N NaOH until the solution is basic, andextract with ether (3×1 L). Wash the organic layer with H₂O, and brine,dry over K₂CO₃, filter, and concentrate. Purify by distillation underreduced pressure (120° C., 0.4 mm Hg). Anal. calc'd for C: 73.70%, H:9.56%, N: 7.81%; Found C: 73.44%, H: 9.36%, N: 7.75%.

Preparation 5 (3-Bromo-propyl)-(2-methyl-benzyl)-amine

In a three neck round bottom flask fitted with a thermometer anddistillation head, add a solution of 48% aqueous HBr (130 mL) to cooled(5° C.) 3-(2-methyl-benzylamino)-propan-1-ol (46.3 g, 0.26 mol). Heatthe resulting solution, distilling off H₂O (91 mL, 110° C. to 124° C.).Cool the solution, filter off the resulting solid, and rinse with H₂O.Recrystallize from iPrOH (500 mL). mp 167-169° C.

Preparation 6 9-Methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepinehydrochloride

Add AlCl₃ (39.9 g, 0.3 mol) to a solution of(3-bromo-propyl)-(2-methyl-benzyl)-amine (3.23 g, 0.10 mol) in decalin(400 mL). Heat the solution to 130° C. for 1 h, then cool in an ice bathand acidify with conc. HCl (100 mL). Wash the resulting solution withether, make the aqueous layer basic with 5 N NaOH, and extract withether (three times). Wash the organic layer with brine, dry over K₂CO₃,filter, and concentrate. Purify the liquid by distillation under reducedpressure (b.p. 116-120° C. at 8 mm Hg). Form the HCl salt andrecrystallize from EtOAc/MeOH, filter and recrystallize again fromiPrOH. m.p. 244-247° C. R_(f)=0.61 (20:1 CHCl₃/MeOH).

Preparation 71-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-chloro-phenyl)-1H-[1,2,3]triazole-4-carboxylicacid

Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-(2-chloro-phenyl)-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (800 mg, 1.67 mmol) in EtOH (7 mL) and add 1N NaOH (3mL, 3 mmol). Warm the mixture to 40° C. and stir overnight. Cool themixture to RT and acidify with IN HCl (5-10 mL). Collect the precipitateby filtration and rinse with H₂O. Dry in a vacuum oven (40° C.)overnight to provide the title compound (680 mg, 90%) as a white solid.R_(f)=0.50 (2:1 CHCl₃/MeOH); MS(ES) 450.1 (M+1)⁺.

By the method of Preparation 7, using the appropriate carboxylic ester,the following compounds are prepared and isolated. Prep. # Product Data8 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(2-fluoro- Rf=0.47(2:1CHCl₃/MeOH); phenyl)-1H-[1,2,3]triazole-4-carboxylic acid MS(ES)434.1(M+1)⁺. 9 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(3- Rf=0.50(2:1CHCl₃/MeOH); trifluoromethyl-phenyl)-1H-[1,2,3]triazole-4-MS(ES):484.1(M+1)⁺. carboxylic acid 101-(3,5-Bis-trifluoromethyl-benzyl)-5-(3-methoxy- Rf=0.60(2:1CHCl₃/MeOH); phenyl)-1H-[1,2,3]triazole-4-carboxylic acidMS(ES):446.1(M+1)⁺. 11 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(4-chloro-Rf=0.57(2:1 CHCl₃/MeOH); phenyl)-1H-[1,2,3]triazole-4-carboxylic acidMS(ES):450.1(M+1)⁺. 12 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(4-fluoro-Rf=0.57(2:1 CHCl₃/MeOH); phenyl)-1H-[1,2,3]triazole-4-carboxylic acidMS(ES):434.1(M+1)⁺. 13 1-(3,5-Bis-trifluoromethyl-benzyl)-5-p-tolyl-1H-Rf=0.70(2:1 CHCl₃/MeOH); [1,2,3]triazole-4-carboxylic acidMS(ES):430.1(M+1)⁺. 14 1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-Rf=0.40(2:1 CHCl₃/MeOH); [1,2,3]triazole-4-carboxylic acidMS(ES):416.1(M+1)⁺. 15 1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-methoxy-MS(ES) 446.1(M+1)⁺; phenyl)-1H-[1,2,3]triazole-4-carboxylic acid m.p.172.4-174.0° C. 16 1-(3,5-bis-trifluoromethyl-benzyl)-5-m-tolyl-1H-MS(ES) 430.1(M+1)⁺; [1,2,3]triazole-4-carboxylic acid m.p. 153.2-156.0°C. 17 1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H- MS(ES)415.2(M+1)⁺. imidazole-4-carboxylic acid 181-Phenethyl-5-phenyl-1H-imidazole-4-carboxylic ¹H NMR(DMSO-d₆, 300mHz) δacid 8.75(s, 1H), 7.25-7.55(m, 5H), 7.05-6.95(m, 2H), 4.20(m, 2H),2.80(m, 2H).

Preparation 19 (2-Chloro-phenyl)-propynoic acid ethyl ester

Dissolve 1-chloro-2-ethynyl-benzene (0.56 g, 4.1 mmol) in THF (16 mL)and cool to −78° C. Add BuLi (3.0 mL of a 1.6 M solution in hexanes, 4.9mmol) dropwise, and stir at −78° C. After 30 min., addethylchloroformate (0.51 mL, 0.58 g, 5.3 mmol) and allow the resultingsolution to warm slowly to RT. After 1 hr, quench with H₂O and extractwith Et₂O. Wash the organic layer with brine, dry (MgSO₄), filter andconcentrate. Use the resulting crude alkynyl ester without furtherpurification. R_(f)=0.49 (10:1 hexanes/EtOAc); ¹H NMR (CDCl₃, 250 MHz)δ7.52 (dd, J=1.5, 7.5 Hz, 1H), 7.30 (m, 2H), 7.18 (td, J=1.5, 7.3 Hz,1H), 4.23 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).

By the method of Preparation 19, using the appropriate alkyne startingmaterial, the following compounds are prepared and isolated: (10:1hexanes/EtOAc) Prep. # Product Data 20 (2-Fluoro-phenyl)-R_(f)=0.38(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) propynoic acidethyl ester δ 7.59(m, 1H), 7.46(m, 1H), 7.21(m, 2H), 4.34(q, J=7.2Hz,2H), 1.42(t, J=7.2Hz, 3H). 21 (3-Trifluoromethyl- R_(f)=0.42(10:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) phenyl)-propynoic acid δ 7.88(s,1H), 7.79(d, J=7.7Hz, 1H), 7.73(d, J=8.0Hz, ethyl ester 1H), 7.55(t,J=7.8, 1H), 4.31(q, J=7.2Hz, 2H), 1.39(t, J=7.2Hz, 3H). 22(3-Methoxy-phenyl)- R_(f)=0.32(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃,250MHz) propynoic acid ethyl ester δ 7.19(d, J=7.7Hz, 1H), 7.15(d,J=3.8Hz, 1H), 7.08(dt, J=1.2, 6.4Hz, 1H), 7.00(dd, J=1.4, 2.4Hz, 1H),6.89(ddd, J=1.2, 2.6, 8.2Hz, 1H), 4.20(q, J=7.1Hz, 2H), 3.71(s, 3H),1.26(t, J=7.1Hz, 3H). 23 (4-Chloro-phenyl)- R_(f)=0.48(10:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) propynoic acid ethyl ester δ7.45(d, J=8.5Hz, 2H), 7.29(d, J=8.5Hz, 2H), 4.23(q, J=7.2Hz, 2H),1.29(t, J=7.2Hz, 3H). 24 (4-Fluoro-phenyl)- R_(f)=0.42(10:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) propynoic acid ethyl ester δ7.52(dd, J=5.3, 8.8Hz, 2H), 7.00(t, J=8.6Hz, 2H), 4.23(q, J=7.1Hz, 2H),1.29(t, J=7.1Hz, 3H). 25 p-Tolyl-propynoic acid R_(f)=0.45(10:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) ethyl ester δ 7.53(d, J=8.2Hz,2H), 7.22(d, J=8.0Hz, 2H), 4.34(q, J=7.1Hz, 2H), 2.42(s, 3H), 1.40(t,J=7.1Hz, 3H). 26 (4-methoxy-phenyl)- MS(ES) 205.0(M+1)⁺; IR: 2207cm−1propynioc acid ethyl ester 27 m-tolyl-propynoic acid MS(ES) 189.1(M+1)⁺;IR: 2218cm−1 ethyl ester 28 pyridin-2-yl-propynoic MS(ES) 176.0(M+1)⁺.¹H NMR(400MHz, CDCl₃):δ acid ethyl ester 8.62(m, 1H), 7.69(dt, 1H,J=2.0, 7.8Hz), 7.56(dt, 1H, J=1.0, 7.8Hz), 7.32(ddd, 1H, J=1.0, 4.9,7.8Hz), 4.28(q, 2H, J=7.3Hz), 1.31(t, 3H, J=7.3Hz).

Preparation 29 N-methyl-N-[3,5-bis-(trifluoromethyl)benzyl]amine

Add methylamine (3.1 mL of a 2M soln in MeOH, 6.2 mmol) to a solution of3,5-bis-trifluoromethyl-benzaldehyde (1.0 g, 4.1 mmol) in MeOH (3 mL).Stir at RT for 12 h, then cool to 0° C. and add NaBH₄ (310 mg, 8.25mmol) in batches (caution: gas evolution). Warm the mixture to RT, andstir overnight. Quench with excess 1N NaOH solution and stir for 30min., then extract with CH₂Cl₂ (2 times). Wash the combined organiclayers with brine, dry over Na₂SO₄, filter, and concentrate. Use thecrude amine without further purification. MS(ES) 258.2 (M+1)⁺;R_(f)=0.45 (10:1 CHCl3/MeOH).

By the method of Preparation 29, using the appropriate amine andaldehyde, the following compounds are prepared and isolated: (10:1CHCl₃/MeOH). Prep. # Product Data 30 N-methyl-N-(2-fluorobenzyl)amineMS(ES) 140.0(M+1)⁺; R_(f)=0.23(10:1 CHCl₃/MeOH); 31N-methyl-N-(4-fluorobenzyl)amine MS(ES) 140.0(M+1)⁺; Rf: 0.11(10:1CHCl3/MeOH) 32 N-methyl-N-(3-methylbenzyl)amine MS(ES) 105.1(M+1)⁺; Rf:0.11(10:1 CHCl₃/MeOH); 33 N-methyl-N-(2-methoxybenzyl)amine MS(ES)152.0(M+1)⁺; Rf: 0.14(10:1 CHCl₃/MeOH); 34N-methyl-N-(3-methoxybenzyl)amine MS(ES) 152.0(M+1)⁺; Rf: 0.12(10:1CHCl₃/MeOH); 35 N-methyl-N-(4-methoxybenzyl)amine MS(ES) 152.1(M+1)⁺;Rf: 0.09(10:1 CHCl₃/MeOH); 36 N-methyl-N-(4-chlorobenzyl)amine MS(ES)156.0(M+1)⁺; Rf: 0.11(10:1 CHCl₃/MeOH); 37N-methyl-N-(3-chlorobenzyl)amine MS(ES) 156.0(M+1)⁺; Rf: 0.17(10:1CHCl₃/MeOH); 38 N-methyl-N-(4-trifluoromethylbenzyl)amine MS(ES)190.1(M+1)⁺; Rf: 0.17(10:1 CHCl₃/MeOH); 39 N-methyl-N-[4-(1- MS(ES)191.1(M+1)⁺; pyrrolidino)benzyl]amine Rf: 0.05(10:1 CHCl₃/MeOH); 40N-methyl-N-[4-(N,N- MS(ES) 165.1(M+1)⁺; dimethylamino)benzyl]amine Rf:0.05(10:1 CHCl₃/MeOH); 41 N-methyl-N-(2-methylbenzyl)amine MS(ES)136.1(M+1)⁺; Rf: 0.17(10:1 CHCl₃/MeOH); 42N-methyl-N-(4-methylbenzyl)amine MS(ES) 136.1(M+1)⁺; Rf: 0.14(10:1CHCl₃/MeOH) 43 N-methyl-N-(3-fluorobenzyl)amine MS(ES) 140.1(M+1)⁺; Rf:0.23(10:1 CHCl₃/MeOH) 44 N-methyl-N-(2- MS(ES) 190.0(M+1)⁺;trifluoromethyl)benzylamine Rf: 0.37(10:1 CHCl₃/MeOH) 45 N-methyl-N-(3-MS(ES) 190.0(M+1)⁺; trifluoromethylbenzyl)amine Rf: 0.23(10:1CHCl₃/MeOH) 46 methylpyridin-2-ylmethylamine MS(ES) 123.1(M+1)⁺; Rf:0.05(10:1 CHCl₃/MeOH) 47 methylpyridin-4-ylmethylamine MS(ES)123.0(M+1)⁺; Rf: 0.05(10:1 CHCl₃/MeOH) 48(±)-N-methyl-N-alpha-methylbenzylamine MS(ES) 136.1(M+1)⁺; Rf: 0.11(10:1CHCl₃/MeOH) 49 (±)-N-methyl-N-alpha-methyl-(3- MS(ES) 170.0(M+1)⁺;chlorobenzyl)amine Rf: 0.20(10:1 CHCl₃/MeOH) 50 N-methyl-N-(2-chloro-6-MS(ES) 174.0(M+1)⁺; fluorobenzyl)amine Rf: 0.37(10:1 CHCl₃/MeOH) 51N-methyl-N-(2,6-dichlorobenzyl)amine MS(ES) 189.9(M+1)⁺; Rf: 0.43(10:1CHCl₃/MeOH) 52 N-methyl-N-(2,3-dichlorobenzyl)amine MS(ES) 189.9(M+1)⁺;Rf: 0.34(10:1 CHCl₃/MeOH) 53 N-methyl-N-(2-chloro-4- MS(ES) 174.0(M+1)⁺;fluorobenzyl)amine Rf: 0.25(10:1 CHCl₃/MeOH) 54N-methyl-N-(2,4-difluorobenzyl)amine MS(ES) 158.0(M+1)⁺; Rf: 0.26(10:1CHCl₃/MeOH) 55 N-methyl-N-(2,6-difluorobenzyl)amine MS(ES) 158.0(M+1)⁺;Rf: 0.37(10:1 CHCl₃/MeOH) 56 N-methyl-N-(2-bromobenzyl)amine MS(ES)140.0(M+1)⁺; Rf: 0.31(10:1 CHCl₃/MeOH) 57 N-methyl-N-(2- MS(ES)199.9(M+)⁺; trifluoromethoxybenzyl)amine Rf: 0.29(10:1 CHCl₃/MeOH) 58N,N-di-(2-chlorobenzyl)amine MS(ES) 266.1(M+1)⁺; Rf: 0.65(10:1CHCl₃/MeOH) 59 N,N-di-(2-fluorobenzyl)amine MS(ES) 234.1(M+1)⁺; Rf:0.59(10:1 CHCl₃/MeOH) 60 (R)-N-(2-chlorobenzyl)-N-(alpha- MS(ES)246.1(M+1)⁺; methylbenzyl)amine Rf: 0.64(10:1 CHCl₃/MeOH) 61(S)-N-(2-chlorobenzyl)-N-(alpha- MS(ES) 246.1(M+1)⁺; methylbenzyl)amineRf: 0.64(10:1 CHCl₃/MeOH); 62 (±)-N-methyl-N-[alpha-methyl-(2- MS(ES)170.0(M+1)⁺; methylbenzyl)]amine Rf: 0.11(10:1 CHCl₃/MeOH); 63(±)-N-methyl-N-[alpha-methyl-(3- MS(ES) 154.1(M+1)⁺; fluorobenzyl)]amineRf: 0.14(10:1 CHCl₃/MeOH); 64 (±)-N-methyl-N-[alpha-methyl-(4- MS(ES)154.1(M+1)⁺; fluorobenzyl)]amine Rf: 0.11(10:1 CHCl₃/MeOH); 65N-ethyl-N-benzylamine MS(ES) 136.1(M+1)⁺; Rf: 0.20(10:1 CHCl₃/MeOH); 66N-ethyl-N-(2-chlorobenzyl)amine MS(ES) 170.0(M+1)⁺; Rf: 0.37(10:1CHCl₃/MeOH); 67 N-methyl-N-(5-chloro-2- MS(ES) 186.1(M+1)⁺;methoxybenzyl)amine Rf: 0.14(10:1 CHCl₃/MeOH); 68N-methyl-N-(2-methoxy-5- MS(ES) 236.1(M+1)⁺;trifluoromethoxybenzyl)amine Rf: 0.17(10:1 CHCl₃/MeOH); 69N-methyl-N-(5-fluoro-2- MS(ES) 170.1(M+1)⁺; methoxybenzyl)amine Rf:0.17(10:1 CHCl₃/MeOH); 70 N-methyl-N-(3-fluoro-5- MS(ES) 208.1(M+1)⁺;trifluoromethylbenzyl)amine Rf: 0.29(10:1 CHCl₃/MeOH); 71N-methyl-N-(3,5-dimethylbenzyl)amine MS(ES) 150.1(M+1)⁺; Rf: 0.14(10:1CHCl₃/MeOH); 72 N-methyl-N-(3,5-dichlorobenzyl)amine MS(ES) 190.0(M+1)⁺;Rf: 0.26(10:1 CHCl₃/MeOH); 73 N′-(2-Chlorobenzyl)-N,N-dimethyl-ethane-MS(ES) 213.2(M+1)⁺; 1,2-diamine Rf: 0.16(10:1 CHCl₃/MeOH); 74(2-Chloro-benzyl)-(2-pyrrolidin-1-yl- MS(ES) 239.2(M+1)⁺; ethyl)-amineRf: 0.21(10:1 CHCl₃/MeOH); 75 (2-Chloro-benzyl)-(2-morpholin-4-yl-MS(ES) 255.2(M+1)⁺; ethyl)-amine Rf: 0.19(10:1 CHCl₃/MeOH); 76(3,5-Bis-trifluoromethyl-benzyl)- MS(ES) 286.1(M+1)⁺; R_(f)=0.39isopropyl-amine (6.7% MeOH/CH₂Cl₂). 77 (3,5-Bis-trifluoromethyl-benzyl)-MS(ES) 284.1(M+1)⁺; R_(f)=0.76 cyclopropyl-amine (6.7% MeOH/CH₂Cl₂).

Preparation 78(±)-N-methyl-N-alpha-methyl-[bis-(3,5-trifluoromethyl)benzyl]amine

Dissolve 3,5-bis(trifluoromethyl)acetophenone (4.97 g, 19.4 mmol) in1,2-dichloroethane (100 mL). Add methylamine (12.5 mL of a 2 M soln. inTHF, 25 mmol) followed by sodium triacetoxyborohydride (8.56 g, 40mmol). Stir the mixture at RT for 3 h., then quench with excesssaturated NaHCO₃ solution. Extract with EtOAc twice and wash thecombined organic layers with brine. Dry over Na₂SO₄, filter, andconcentrate. Use the crude amine without further purification. MS(ES)272.1 (M+1)⁺; R_(f)=0.54 (10:1 CHCl₃/MeOH).

By the method of Preparation 78, using the appropriate amine and ketoneor aldehyde, the following compounds are prepared and isolated: Prep. #Product Data 79 (±)-1-methylamino-indane MS(ES) 148.1(M+1)⁺; Rf:0.11(10:1 CHCl₃/MeOH); 80 (±)-1-methylamino-1,2,3,4- MS(ES) 162.1(M+1)⁺;tetrahydronaphthylene Rf: 0.14(10:1 CHCl₃/MeOH); 81(±)-2-methylamino-1,2,3,4- MS(ES) 162.1(M+1)⁺; tetrahydronaphthylene Rf:0.14(10:1 CHCl₃/MeOH); 82 (±)-2-(N-methyl- MS(ES) 186.1(M+1)⁺;aminomethyl)naphthylene Rf: 0.17(10:1 CHCl₃/MeOH); 83N-benzyl-N-propylamine MS(ES) 150.1(M+1)⁺; Rf: 0.23(10:1 CHCl₃/MeOH); 84N-benzyl-N-isopropylamine MS(ES) 150.1(M+1)⁺; Rf: 0.26(10:1 CHCl₃/MeOH);85 N-benzyl-N-cyclopropylamine MS(ES) 148.1(M+1)⁺; Rf: 0.49(10:1CHCl₃/MeOH); 86 N-(2-chlorobenzyl)-N- MS(ES) 184.1(M+1)⁺; propylamineRf: 0.40(10:1 CHCl₃/MeOH); 87 N-(2-chlorobenzyl)-N- MS(ES) 184.1(M+1)⁺;isopropylamine Rf: 0.46(10:1 CHCl₃/MeOH); 88 N-(2-chlorobenzyl)-N-MS(ES) 182.1(M+1)⁺; cyclopropylamine Rf: 0.63(10:1 CHCl₃/MeOH); 89N-isopropyl-N-(2- MS(ES) 234.1(M+1)⁺. trifluoromethoxybenzyl)-amine

Preparation 90 Indan-2-yl -methyl-amine

Add triethylamine (4.7 g, 46.8 mmol) and ethyl chloroformate (2.46 mL,25.7 mmol) to a solution of 2-aminoindan (3.12 g, 23.4 mmol) in THF(0.1M). After 1 hr, dilute with EtOAc (200 mL), wash with 1 N HCl (200mL), and brine (200 mL), dry over Na₂SO₄, filter, and concentrate.Dissolve the residue in THF (50 mL) and slowly add LiAlH₄ (94 mL of a 1Msoln in THF, 94 mmol). Warm the resulting mixture to reflux. After 3 h.,cool to RT and add H₂O (3.6 mL). Stir for 2 min., then add 1N NaOH (3.6mL) and stir for 5 min. Add more H₂O (10.8 mL) and stir another 5 min.Finally, add Celite and Na₂SO₄, stir 5 min, then filter and concentratethe filtrate to give the title compound. Use without furtherpurification. MS(ES) 148.2 (M+1)⁺; R_(f)=0.18 (10:1 CHCl₃/MeOH).

By the method of Preparation 90, using the appropriate amine, thefollowing compounds are prepared and isolated: Prep. # Product Data 91(1-benzyl-piperidin-4-yl)- MS(ES) 205.3(M+1)⁺; methyl-amine Rf:0.10(10:1 CHCl₃/MeOH); 92 [2-(2-chlorophenyl)-ethyl]- MS(ES)170.1(M+1)⁺; methyl-amine Rf: 0.22(10:1 CHCl₃/MeOH);

Preparation 93 3-Phenyl-propynoic acid benzyl-methyl-amide

Suspend phenylpropiolic acid (4.2 g, 28.7 mmol) and1-hydroxybenzotriazole hydrate (4.3 g, 32 mmol) in dry CH₂Cl₂ (250 mTL).Add N-benzyl-N-methylamine (3.5 g, 29 mmol) and triethylamine (20 mL,145 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (6.1 g, 32 mmol). Stir at RT overnight, then dilute withCH₂Cl₂, wash with 1N HCl solution, saturated NaHCO₃ solution, and brine.Dry the organic layer over MgSO₄, filter, and concentrate to give thetitle compound (3.36 g, 47%) as a yellow oil that solidifies uponstanding. Use without further purification. R_(f)=0.38 (2:1hexanes/EtOAc); MS(ES) 250.1 (M+1)⁺.

By the method of Preparation 93, using the appropriate amine, thefollowing compounds are prepared and isolated. Prep. # Product Data 943-Phenyl-propynoic acid (3,5-bis- Rf=0.42(2:1 hexanes/EtOAc);trifluoromethyl-benzyl)-methyl-amide MS/ES:386.1(M+1)⁺. 953-Phenyl-propynoic acid (3,5-dimethyl-benzyl)- Rf=0.41(2:1hexanes/EtOAc); methyl-amide MS/ES:278.1(M+1)⁺. 96 3-Phenyl-propynoicacid (3,5-dichloro-benzyl)- Rf=0.42(2:1 hexanes/EtOAc); methyl-amideMS(ES) 318.1(M+1)⁺. 97 3-Phenyl-propynoic acid (5-chloro-2-methoxy-Rf=0.32(2:1 hexanes/EtOAc); benzyl)-methyl-amide MS(ES) 314.1(M+1)⁺. 983-Phenyl-propynoic acid (5-fluoro-2-methoxy- Rf=0.31(2:1 hexanes/EtOAc);benzyl)-methyl-amide MS(ES) 298.1(M+1)⁺. 99 3-Phenyl-propynoic acid(2-methoxy-5- Rf=0.32(2:1 hexanes/EtOAc);trifluoromethoxy-benzyl)-methyl-amide MS(ES) 364.1(M+1)⁺. 1003-Phenyl-propynoic acid (3-fluoro-5- Rf=0.45(2:1 hexanes/EtOAc);trifluoromethyl-benzyl)-methyl-amide MS(ES) 336.1(M+1)⁺. 1013-Phenyl-propynoic acid (2-chloro-benzyl)- Rf=0.42(2:1 hexanes/EtOAc);methyl-amide MS(ES) 284.1(M+1)⁺. 102 3-Phenyl-propynoic aciddibenzyl-amide Rf=0.62(2:1 hexanes/EtOAc); MS(ES) 326.2(M+1)⁺. 1033-Phenyl-propynoic acid methyl-phenethyl- Rf=0.32(2:1 hexanes/EtOAc);amide MS(ES) 264.2(M+1)⁺.

Preparation 104 1-(2-azido-ethyl)-4-fluoro-benzene

Dissolve the 1-(2-chloroethyl)-4-fluorobenzene (1 eq) in DMSO/H₂O(10:1). Add NaN₃ (2 eq) and stir at RT overnight. Dilute with ether,wash with H₂O, and brine. Dry (MgSO₄), and concentrate to give the titlecompound. Use crude compound without urification. R_(f)=0.48(20:1hexanes/EtOAc); IR: 2104 cm-1.

By the method of Preparation 104, using the appropriate startingmaterials, the following compounds are prepared and isolated. Prep. #Product Data 105 1-azidomethyl-3,5-bis- Rf=0.42(20:1 hexanes/EtOAc);IR:2105cm−1 trifluoromethyl-benzene 106 3,5-dimethylbenzyl azideRf=0.68(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.03(s, 1H),6.96(s, 2H), 4.30(s, 2H), 2.37(s, 6H). 107 3,5-dichlorobenzyl azideRf=0.57(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.36(m, 1H),7.25(s, 2H), 4.36(s, 2H). 108 3-phenylpropyl azide Rf=0.57(20:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.05-7.25(m, 5H), 3.19(t, 2H),2.62(t, 2H), 1.83(quint, 2H). 109 (4-methoxyphenyl)propyl Rf=0.40(20:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) azide δ 7.14(d, 2H), 6.88(d, 2H),3.83(s, 3H), 3.31(t, 2H), 2.69(t, 2H), 1.92(quint, 2H). 110 1-[4-(2-Rf=0.11(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) azidoethyl)phenyl]-1-δ 7.91(d, 2H), 7.32(d, 2H), 3.54(t, 2H), 2.93(t, ethanone 2H), 2.67(s,3H). 111 4-azidomethylbiphenyl Rf=0.49(20:1 hexanes/EtOAc); ¹HNMR(CDCl₃, 250MHz) δ 7.52(m, 4H), 7.25-7.4(m, 5H), 4.29(s, 2H). 1124-(azidomethyl)-2,6- Rf=0.24(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz)dichloropyridine δ 7.22(s, 2H), 4.37(s, 2H). 113 2-chlorobenzyl azideRf=0.60(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.45(m, 2H),7.34(m, 2H), 4.54(s, 2H). 114 1-phenethyl azide Rf=0.61(20:1hexanes/EtOAc); ¹H NMR(CDCl₃, 300MHz) δ 7.3-7.4(m, 5H), 4.62(q, J=6.8Hz,1H), 1.54(d, J=6.8Hz, 3H). 115 3-fluorobenzyl azide Rf=0.51(20:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.38(m, 1H), 7.10(m, 3H),4.39(s, 2H). 116 3-(trifluoromethyl)benzyl Rf=0.46(20:1 hexanes/EtOAc);¹H NMR(CDCl₃, 250MHz) azide δ 7.5-7.7(m, 4H), 4.47(s, 2H). 1172-(trifluoromethyl)benzyl Rf=0.60(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃,250MHz) azide δ 7.69(d, 1H), 7.62(m, 2H), 7.49(m, 1H), 4.61(s, 2H). 1181-(azidomethyl)- Rf=0.51(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz)napthylene δ 8.07(d, 1H), 7.92(m, 2H), 7.45-7.65(m, 4H), 4.81(s, 2H).119 3-chlorobenzyl azide Rf=0.54(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃,300MHz) δ 7.32(m, 3H), 7.21(m, 1H), 4.33(s, 2H). 120 2-phenethyl azideRf=0.60(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 300MHz) δ 7.2-7.35(m, 5H),3.48(t, 2H), 2.87(t, 2H). 121 benzyl azide Rf=0.58(20:1 hexanes/EtOAc);¹H NMR(CDCl₃, 300MHz) δ 7.25-7.42(m, 5H), 4.33(s, 2H). 1224-methoxybenzyl azide Rf=0.38(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 300MHz)δ 7.25(d, 2H), 6.91(d, 2H), 4.27(s, 2H), 3.82(s, 3H). 1233,5-dibromobenzyl azide Rf=0.57(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃,250MHz) δ 7.67(s, 1H), 7.44(s, 2H), 4.35(s, 2H). 1242-(4-methoxyphenyl)ethyl Rf=0.40(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃,250MHz) azide δ 7.17(d, 2H), 6.90(d, 2H), 3.84(s, 3H), 3.51(t, 2H,2.88(t, 2H). 125 (±)-2-azido-1- Rf=0.63(20:1 hexanes/EtOAc); ¹HNMR(CDCl₃, 250MHz) phenylpropane δ 7.2-7.4(m, 5H), 3.73(m, 1H), 2.88(dd,1H), 2.77(dd, 1H), 1.30(d, 3H). 126 2-methylbenzyl azide Rf=0.60(20:1hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.15(m, 4H), 4.21(s, 2H),2.29(s, 3H). 127 3-methylbenzyl azide Rf=0.60(20:1 hexanes/EtOAc); ¹HNMR(CDCl₃, 250MHz) δ 7.18(m, 1H), 7.05(m, 3H), 4.22(s, 2H), 2.30(s, 3H).128 4-methylbenzyl azide Rf=0.62(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃,250MHz) δ 7.12(s, 4H), 4.21(s, 2H), 2.28(s, 3H). 129 2-bromobenzyl azideRf=0.57(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.53(d, 1H),7.30(m, 2H), 7.13(m, 1H), 4.41(s, 2H). 130 2-methoxybenzyl azideRf=0.49(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.17(m, 2H),6.34(m, 2H), 4.24(s, 2H), 3.73(s, 3H). 131 3-methoxybenzyl azideRf=0.40(20:1 hexanes/EtOAc); ¹H NMR(CDCl₃, 250MHz) δ 7.21(t, 3H),6.77(m, 3H), 4.22(s, 2H), 3.72(s, 3H).

Preparation 132 2-(2-methyoxyphenyl)ethyl azide

Add pyridine (3.1 g, 39.4 mmol), p-toluenesulfonyl chloride (1.50 g, 7.9mmol), and DMAP (50 mg) to a solution of 2-(2-methoxyphenyl)ethylalcohol (1.0 g, 6.6 mmol) in CH₂Cl₂(0.2M) (25 mL). Allow mixture to stirovernight at RT, then dilute with ether (250 mL) and wash with saturatedNaHCO₃ (2×150 mL) and brine. Dry over MgSO₄, filter, and concentrate.

Dissolve the crude residue in DMSO (7 mL), add H₂O (0.7 mL), and NaN₃(850 mg, 13.2 mmol). Warm the mixture to 50° C. and stir for 48 h, thencool to RT and dilute with ether. Wash twice with H₂O, and then withbrine, dry over Na₂SO₄, filter, and concentrate to give the titlecompound as a pale yellow oil. Use without further on. R_(f)=0.43 (10:1hexanes/EtOAc); ¹H NMR (CDCl₃, 250 MHz) δ7.11 (m, 2H), 6.80 (m, 2H),3.75 (s, 3H), 3.38 (t, 2H), 2.85 (t, 2H).

By the method of Preparation 132, using the appropriate alcohol, thefollowing compounds are prepared and isolated. Prep. # Product Data 1332-[3,5-bis(trifluoromethyl)- Rf=0.37(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃,phenyl]ethyl azide 250MHz) δ 7.71(s, 1H), 7.62(s, 2H), 3.53(t, 2H),2.93(t, 2H). 134 2,2-diphenylethyl azide Rf=0.41(10:1 hexanes/EtOAc); ¹HNMR(CDCl₃, 250MHz) δ 7.2-7.5(m, 10H), 4.28(t, 1H), 3.93(d, 2H). 1352-(3-methylphenyl)ethyl Rf=0.52(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃, azide250MHz) δ 7.23(m, 1H), 7.04(m, 3H), 3.50(t, 2H), 2.87(t, 2H), 2.35(s,3H). 136 2-[(3- Rf=0.47(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃,trifluoromethyl)phenyl] 250MHz) δ 7.4-7.6(m, 4H), 3.55(t, 2H), 2.95(t,ethyl azide 2H). 137 2-[(4- Rf=0.28(10:1 hexanes/EtOAc); ¹H NMR(CDCl₃,dimethylamino)phenyl] 250MHz) δ 7.00(d, 2H), 6.61(d, 2H), 3.35(t, 2H),ethyl azide 2.83(s, 6H), 2.71(t, 2H).

Preparation 138 1-(3-methylphenyl)-1-azidoethane

Dissolve 1-(3-methylphenyl)-1-ethanol (1.36 g, 10 mmol) in dry toluene.Cool to 0° C. and add DPPA (diphenylphosphoryl azide, 3.3 g, 12 mmol)followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.8 mL, 12 mmol).Warm the resulting mixture to RT and stir overnight, then dilute withH₂O, and extract with ether. Wash the organic layer with 1 N HCl,saturated NaHCO₃, and brine. Dry over MgSO₄, filter, and concentrate togive the title compound (1.3 g, 81%) as a pale yellow oil. Use withoutfurther purification. R_(f)=0.66 (20:1 hexanes/EtOAc); ¹H NMR (CDCl₃,250 MHz) δ7.1-7.4H), 4.61 (q, 1H), 2.42 (2, 3H), 1.56 (d, 3H).

By the method of Preparation 138, using the appropriate alcohol startingmaterial, the following compounds are prepared and isolated. Prep. #Product Data 139 1-(4-fluorophenyl)-1- Rf=0.63(10:1 hexanes/EtOAc); ¹Hazidoethane NMR(CDCl₃, 250MHz) δ 7.2-7.4(m, 2H), 7.1(t, 2H), 4.64(q,1H), 1.55(d, 3H). 140 (±)-1-[(3- Rf=0.60(20:1 hexanes/EtOAc); ¹Htrifluoromethyl)phenyl]- NMR(CDCl₃, 250MHz) 1-azidoethane δ 7.5-7.7(m,3H), 7.35(m, 1H), 4.73(q, 1H), 1.59(d, 3H).

Preparation 141 1-(2-Chloro-phenyl)-pyrazolidin-3-one

Dissolve sodium metal (1.5 g, 64.4 mmol) in n-butanol (25 mL) then add2-chlorophenylhydrazine hydrochloride (5.0 g, 28.0 mmol). To thismixture, add methyl acrylate (3.8 mL, 42.0 mmol) in a dropwise fashion,then warm the mixture to reflux. After 5 h., add water (100 mL) whilethe solution is still hot, then adjust the pH of the solution with topH=6 with 50% aqueous acetic acid. Wash with water and filter theprecipitate. Rinse the precipitate with ether and dry on vacuum pump toafford 3.67 g (67%) of the title compound as a white solid. MS(ES) 197.1(M+1)⁺; R_(f)=0.4

Preparation 142 (2-Chloro-4-methyl-phenyl)-methyl-amine

Stir 2-chloro-4-methylaniline (5.0 g, 35.5 mmol) and methyl iodide (2.2mL, 35.5 mmol) neat at RT. After 12 h, add water and extract with EtOAc.Wash the organic layer with saturated aqueous NaHCO₃, and brine, dryover sodium sulfate, filter, and concentrate. Purify by chromatographyon SiO₂ (EtOAc/hexanes gradient) to afford 3.4 g of a 1:1 mix of thetitle compound and N,N-dimethyl material. Use the mixture withoutfurther purification. IS (MS) 156.1 (M+1)⁺; R_(f)=0.90 (20%EtOAc/hexanes).

Preparation 143 N′-(2-Chloro-phenyl)-hydrazinecarboxylic acid tert-butylester

Dissolve o-chlorophenylhydrazine hydrochloride (5.0 g, 28.0 mmol),potassium carbonate (138 g, 11.6 mmol) and di-t-butyl-dicarbonate (11.6g, 84.0 mmol) in THF (50 mL) and water (50 mL) and stir at RT. After 4days, evaporate off the organics, add 20% iPrOH/CHCl₃ and wash withsaturated aqueous NaHCO₃, and brine. Dry the organic layer over sodiumsulfate, filter, and concentrate to dryness. Purify the residue bychromatography using an EtOAc/hexanes gradient to afford the titlecompound (5.65 g, 83%) as a white solid. MS(ES) 241.0 (M−1)⁻; R_(f)−0.13(10% EtOAc/hexanes).

Preparation 144 2-(2-Chloro-phenyl)-pyrazolidine-1-carboxylic acidtert-butyl ester

Dissolve sodium hydride (1.1 g, 27.2 mmol) and 1,3-dibromopropane (1.4mL, 13.6 mmol) in DMF (100 mL) at 0° C. AddN′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (3.3 g,13.6 mmol) and stir at 0° C. After 1 h, quench with water andconcentrate to dryness. Dissolve the residue in 20% iPrOH/CHCl₃ and washwith water. Extract the aqueous layer with CHCl₃ and wash the combinedorganics with saturated aqueous NaHCO₃, and brine. Dry over sodiumsulfate, filter, and concentrate to dryness. Purify the residue bychromatography using an EtOAc/hexanes gradient to afford the titlecompound (3.83 g, 99%) as a yellow oil. MS(ES) 283.1 (M+1)⁺; R_(f)=0.81(1:1 EtOAc/hexanes).

Preparation 145 1-(2-Chloro-phenyl)-pyrazolidine hydrochloride

Dissolve 2-(2-chloro-phenyl)-pyrazolidine-1-carboxylic acid tert-butylester (3.84 g, 13.6 mmol) in a solution of acetic acid saturated withHCl (30 mL) and stir at RT. After 16 h, concentrate the mixture todryness. Slurry the residue in 1,2-dichloroethane and concentrate todryness twice. Triturate with ether, filter the precipiate and dry undervacuum to afford the title compound (2.14 g, 72%). MS(ES) 183.0 (M+1)⁺;Anal. calc'd for C₉H₁₁ClN₂.HCl: C, 49.33; H, 5.52; N, 12.79. Found: C,49.28; H, 5.57; N, 12.70.

Preparation 146 (2-Chloro-4-fluoro-phenyl)-methyl-amine

Using a method similar to Preparation 142, with the exception of using2-chloro-4-fluoroaniline (5.0 g, 34.5 mmol, Aldrich) and methyl iodide(2.2 mL, 34.5 mmol), affords 3.4 g of an approximate 1:1 mix of thetitle compound and N,N-dimethyl material. Carried on as is withoutfurther purification. MS(ES) 160.0 (M+1)⁺; R_(f)=0.9 (20%EtOAc/hexanes).

Preparation 147 2-Chloropyridine-3-carboxaldebyde

Prepare lithium diisopropylamide by the addition of n-butyl lithium(37.5 mL, 0.06 mol, 1.6 M in hexanes) to a solution of diisopropylamine(8.39 mL, 0.06 mol) in THF (150 mL). Cool the mixture to −70° C. and add2-chloropyridine (4.96 mL, 0.05 mol) dropwise via syringe whilestirring. After 1.5 h., add DMF (7.73 mL, 0.10 mol) dropwise viasyringe. After another 1.5 h., remove the cooling bath and quench withwater as the mixture warms to −25° C. Extract the mixture with EtOAc,dry over sodium sulfate, filter, and concentrate in vacuo. Purify theresidue by chromatography on silica gel using 10% EtOAc/hexanes toprovide the title aldehyde (2.58 g, 37%) as an off white solid. MS(EI)140.99 (M⁺); ¹H NMR (d₆ DMSO, 300 MHz) δ10.28 (s, 1H), 8.67 (dd, 1H,J=2.2, 4.8 Hz), 8.27 (dd, 1H, J=2.2, 7.7 Hz), 7.60-7.70 (m, 1H).

Preparation 148 (2-Chloro-pyridin-3-ylmethyl)-methyl-amine

Dissolve 2-chloropyridine-3-carboxaldehyde (2.50 g, 17 mmol) in MeOH (20mL) and add methylamine (15.0 mL of a 2M in MeOH,30 mmol). Stir theresulting mixture at RT. After 24 h, cool the reaction mixture in an icebath and add sodium borohydride (5.25 g, 0.139 mol) in small portions.Stir the mixture for 2 h., then concentrate in vacuo. Add water, andextract with CH₂Cl₂. Dry the organic extracts over Na₂SO₄, filter, andconcentrate. Purify the residue by chromatography on silica gel elutingwith a MeOH/CH₂Cl₂ gradient to obtain the title compound (2.23 g, 85%)as a light oil. MS(EI) 156.0 (M⁺); ¹H NMR (d₆ DMSO, 300 MHz) δ8.25-8.30(m, 1H), 7.87-7.95 (m, 1H), 7.40-7.45 (m, 1H), 3.70 (s, 2H), 2.30 (s,3H).

Preparation 149 3-chloropyridine-4-carboxaldehyde

Using a method similar to Preparation 147, with the exception of using3-chloropyridine (4.75 mL, 0.05 mol), affords the title compound as alight yellowish solid. MS(EI) 141.0 (M⁺); ¹H NMR (d₆ DMSO, 300 MHz)δ10.32 (s, 1H), 8.87 (s, 1H), 8.77 (d, 1H, J=4.8 Hz), 7.75 (d, 1H, J=4.8Hz).

Preparation 150 (3-Chloro-pyridin-4-ylmethyl)-methyl-amine

Using a method similar to Preparation 148, with the exception of using3-chloropyridine-4-carboxaldehyde (2.00 g, 0.014 mol), affords the titlecompound as a light oil. MS(EI) 156.0 (M⁺); ¹H NMR (d₆ DMSO, 300 MHz)δ8.55 (s, 1H), 8.48 (d, 1H, J=4.8 Hz), 7.54 (d, 1H, J=4.8 Hz), 3.79 (s,2H), 2.31 (s, 3H).

Preparation 151 4-Chloropyridine-3-carboxaldehyde

Using a method similar to Preparation 147, with the exception of using4-chloropyridine hydrochloride (3.75 g, 0.025 mol), affords the titlecompound as a light orange solid. MS(ES) 142.0 (M+1)⁺; R_(f)=0.37 (6%MeOH/CH₂Cl₂).

Preparation 152 (4-Chloro-pyridin-3-ylmethyl)-methyl-amine

Using a method similar to Preparation 148, with the exception of using4-chloropyridine-3-carboxaldehyde (0.80 g, 0.0056 mol), affords thetitle compound as a light oil. MS(EI) 156.0 (M⁺); ¹H NMR (d₆ DMSO, 300MHz) δ8.60 (s, 1H), 8.42 (d, 1H, J=5.1 Hz), 7.50 (d, 1H, J=5.1 Hz), 3.75(s, 2H), 2.29 (s, 3H).

Preparation 153 1-Phenethyl-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine ethyl benzoylacetate (1.49 g, 7.76 mmol), 2-phenethyl azide(0.87 g, 6.44 mmol), and potassium carbonate (3.56 g, 25.8 mmol) in DMSO(16 mL) and heat at 50° C. overnight. Dilute the reaction mixture withwater and extract with EtOAc. Wash the combined extracts with brine, dryover Na₂SO₄, filter, and concentrate. Purify the residue bychromatography over silica gel using a hexanes/EtOAc gradient to providethe title compound (0.895 g, 43%) as a pale yellow oil. MS(ES) 322.0(M+1)⁺; Anal. Calc'd for C₁₉H₁₉N₃O₂: C, 71.00; H, 5.96; N, 13.07. Found:C, 71.30; H, 5.84; N, 13.06.

Preparation 154 (3-Chloro-pyridin-4-yl)-isopropyl-amine

Combine 3-chloro-4-aminopyridine (3.00 g, 14.6 mmol) and 2-bromopropane(2.20 mL, 23.4 mmol) in a sealed tube and heat the mixture overnight at100-110° C. Cool the mixture to RT, add aqueous NaHCO₃, and extract withEtOAc. Dry the combined extracts over Na₂SO₄, filter, and concentrate.Purify the residue by chromatography over silica gel using CH₂Cl₂ toprovide the title compound (1.72 g, 69%) as a light oil. MS(ES) 170.2(M+1)⁺; R_(f)=0.71 (25% EtOAc/hexanes).

Preparation 1551-(3,5-Bis-trifluoromethyl-benzyl)-5-methyl-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine ethyl acetoacetate (10.0 g, 77.0 mmol),3,5-bis-trifluoromethyl-benzyl azide (40.3 g, 150 mmol), and potassiumcarbonate (43 g, 308 mmol) in DMSO (100 mL). Stir 4 days at 50° C., thenadd water and extract with EtOAc. Wash with water, and brine, dry oversodium sulfate, filter, and concentrate. Dissolve the residue in warmEtOAc (20 mL) and place in a freezer. After 4 h, add hexanes and collectthe crystalline material by filtration. Dry under vacuum to afford 21.7g (74%) of the title compound as a white solid. MS(ES) 382.0 (M+1);R_(f)=0.55 (1:1 EtOAc/hexanes).

Preparation 156 (R)-(+)-2-(2-chlorophenyl)-pyrrolidine

To a dry Schlenk flask under nitrogen is added 0.540 goof(R,R)-(+)-ethylene-1,2-bis(η⁵-4,5,6,7-tetrahydro-1-indenyl)titaniumdifluoride and 120 mL of dry THF. To this solution are added undernitrogen in the following order: 2-(2-chlorophenyl)-pyrroline (15 g),phenylsilane (15 g), pyrrolidine (0.48 mL), and MeOH (0.24 mL). Thesolution is stirred at RT for 48 h., then the mixture is diluted with350 mL of diethylether and carefully added with vigorous stirring to1200 mL of 1M HCl. The aqueous layer is separated and extracted withthree portions of diethyl ether (300 mL each). The aqueous layer is madebasic with 3M NaOH and extracted with 5 portions of diethyl ether (200mL each). The combined ether layers are dried over magnesium sulfate andconcentrated in vacuo. The residue is purified by vacuum transfer togive the title compound (15 g, 93%) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ7.61-7.58 (m, 1H), 7.32-7.30 (m, 1H), 7.26-7.21 (m, 1H),7.16-7.11 (m, 1H), 4.53 (t, J=, 1H), 3.21-3.16 (m, 1H), 310-3.03 (m,1H), 2.37-2.28 (m, 1H), 2.04 (br s, 1H), 1.93-1.70 (m,2H), 1.60-1.51 (m,1H). ^(13 C NMR ()100 MHz, CDCl₃) 25.7, 33.1, 47.2, 59.0, 127.0, 127.4,127.8, 129.5, 133.1, 143.2.

MS(ES) 182 (M+1)⁺; [α]_(D)=+70.4 (c=0.06, MeOH).

Preparation 1571-(3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine a solution of sodium ethoxide (5.5 mL, 21 wt % in EtOH) anddiethyl malonate (2.50 mL, 16.5 mmol) in EtOH (26 mL) with a solution of1-azidomethyl-3,5-bis-trifluoromethyl-benzene (4.40 g, 16.3 mmol) inEtOH (6 mL) and heat to 80° C. After 7 h, cool to RT and concentrate themixture under reduced pressure. Dissolve the viscous oil in H₂O (20 mL),and add 1N HCl until the solution reaches pH 2. Collect the precipitateby filtration and dry under reduced pressure to give the title compound(5.42 g, 87%) as a white solid, MS(ES) 384.0 (M+1)⁺; ¹H NMR (400 MHz,CHCl₃) δ8.05 (s, 1H), 7.92 (s, 2H), 5.41 (s, 2H), 4.15 (q, 2H, J=7.3Hz), 1.22 (t, 3H, J=7.3 Hz).

Preparation 1581-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]tri-azole-4-carboxylicacid ethyl ester

Add PCl₅ (5.73 g, 27.5 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (5.30 g, 13.8 mmol) in toluene (150 mL) and heat to 50°C. After 2 h, cool the mixture to RT and concentrate under reducedpressure. Dissolve the residue in ether (100 mL) and wash with saturatedNaHCO₃ (2×100 mL) and brine (100 mL), then dry, filter, and concentrate.Purify the crude material by passing through a short plug of silica gelusing a linear gradient of 50% to 80% EtOAc/hexanes. Recrystallize from1:1 diethyl ether:petroleum ether (150 mL) to afford the title compound(3.90 g, 70%) as white plates. MS(ES) 402.0 (M+1)⁺; ¹H NMR (400 MHz,CHCl₃) δ7.88 (s, 1H), 7.76 (s, 2H), 5.67 (s, 2H), 4.43 (q, 2H, J=7.0Hz), 1.40 (t, 3H, J=7.0 Hz).

Preparation 1591-(3,5-Bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

Combine 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (340 mg, 1.26mmol) with a solution of ethyl propiolate (160 mg, 1.63 mmol) in toluene(3.0 mL) and heat to 100° C. for 18 h in a sealed tube. Cool thesolution to RT, concentrate in vacuo, and purify the residue bychromatography using a linear gradient of 15% to 50% EtOAc/hexanes toafford the title compound (233 mg, 50%) as a clear, viscous oil thatsolidified upon standing. MS(ES) 368.2 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃)δ8.08 (s, 1H), 7.78 (s, 1H), 7.73 (s, 2H), 5.70 (s, 2H), 4.41 (q, 2H,J=6.8 Hz), 1.39 (t, 3H, J=7.3 Hz).

Using an analogous method to Preparation 159, with the appropriatestarting materials, yields the following compounds. Prep. # Product Data160 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 368.1(M+1)⁺.methyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester 1611-(3,5-Bis-trifluoromethyl-benzyl)-5-ethyl- MS(ES) 396.1(M+1)⁺.1H-[1,2,3]tri-azole-4-carboxylic acid ethyl ester 1621-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 396.1(M+1)⁺.propyl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester 1631-(3,5-Bis-trifluoromethyl-benzyl)-5-butyl- MS(ES) 410.1(M+1)⁺.1H-[1,2,3]triazole-4-carboxylic acid methyl ester 1641-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 434.1(M−1)⁻.trifluoromethyl-1H-[1,2,3]triazole-4- carboxylic acid ethyl ester 1651-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES) 445.2(M+1)⁺; ¹Hpyridin-2-yl-1H-[1,2,3]triazole-4-carboxylic NMR(400MHz, CDCl₃) δ8.74(m, 1H), acid ethyl ester 7.78(dt, 1H, J=2.0, 7.8Hz), 7.73(m, 2H),7.56(s, 2H), 7.40(ddd, 1H, J=1.5, 4.9, 7.3Hz), 5.91(s, 2H), 4.37(q, 2H,J=7.3Hz), 1.35(t, 3H, J=7.3Hz).

Preparation 1661-(3,5-Bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid

Combine lithium hydroxide monohydrate (260 mg, 6.20 mmol) with asolution of1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester (230 mg, 0.626 mmol) in 2:1 dioxane H₂O (6.75 mL) and stirat RT for 3 h. Dilute solution with H₂O (10 mL) and treat with aqueous1N HCl until pH 3 is obtained. Collect white precipitate by filtrationand dry in vacuo to afford the title compound (195 mg, 92%) as a whitepowder. MS[EI⁻] 338.1 (M−H)⁻. ¹H NMR (400 MHz, DMSO-d₆) δ8.06 (s, 1H),7.31 (s, 1H), 7.30 (s, 2H), 5.04 (s, 2H).

Using a method analogous to Preparation 166, with the appropriatestarting materials, the following compounds may be prepared. Prep. #Product Data 167 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS[EI⁻]352.1(M−H)⁻ methyl-1H-[1,2,3]triazole-4-carboxylic acid 1681-(3,5-Bis-trifluoromethyl-benzyl)-5- MS[EI−] 366.2(M−H)⁻.ethyl-1H-[1,2,3]triazole-4-carboxylic acid 1691-(3,5-Bis-trifluoromethyl-benzyl)-5- MS[EI−] 380.2(M−H)⁻.propyl-1H-[1,2,3]triazole-4-carboxylic acid 1701-(3,5-Bis-trifluoromethyl-benzyl)-5- MS[EI+] 396.1(M+H)⁺, MS[EI−]butyl-1H-[1,2,3]triazole-4-carboxylic acid 394.2(M−H)⁻. 1711-(3,5-Bis-trifluoromethyl-benzyl)-5- MS[EI−] 406.1(M−H)⁻trifluoromethyl-1H-[1,2,3]triazole-4- carboxylic acid 1721-Phenethyl-5-phenyl-1H-[1,2,3]triazole- MS(ES) 294.0(M+1)⁺; Anal.Calc'd 4-carboxylic acid for C₁₇H₁₅N₃O₂.0.35H₂O: C, 68.15; H, 5.28; N,14.02. Found: C, 67.87; H, 5.08; N, 14.44. 1731-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 371.8(M−1)⁻; ¹H NMR(400MHz,chloro-1H-[1,2,3]triazole-4-carboxylic DMSO-d6) δ 12.7(br s, 1H), acid7.33(s, 1H), 7.22(s, 2H), 5.07(s, 2H). 1741-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 410.2(M−1)⁻. ¹HNMR(400MHz, butoxy-1H-[1,2,3]triazole-4-carboxylic CHCl₃) δ 7.86(s, 1H),7.77(s, acid 2H), 5.43(s, 2H), 4.69(m, 2H), 1.63(m, 2H), 1.33(m, 2H),1.23(m, 2H), 0.89(t, 3H, J=6.8Hz). 1755-Benzyloxy-1-(3,5-bis-trifluoromethyl- MS(ES−) 444.2(M−1)⁻. ¹HNMR(400MHz, benzyl)-1H-[1,2,3]triazole-4-carboxylic CHCl₃) δ 7.82(s,1H), 7.60(s, acid 2H), 7.22-7.30(m, 5H), 5.69(s, 2H), 5.29(s, 2H). 1761-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 384.0(M+1)⁺.ethoxy-1H-[1,2,3]triazole-4-carboxylic acid 1771-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 398.1(M+1)⁺propoxy-1H-[1,2,3]triazole-4-carboxylic acid 1785-Chloro-1-(3,5-dichloro-benzyl)-1H- MS(FAB) 305.9(M+1)⁺.[1,2,3]triazole-4-carboxylic acid 1791-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 405.2(M+1)⁺; ¹H NMR(400MHz,pyrrol-1-yl-1H-[1,2,3]triazole-4- DMSO-d6) δ 13.16(br s, carboxylic acidCOOH), 8.03(s, 1H), 7.64(s, 2H), 6.97(t, 2H, J=2Hz), 6.23(t, 2H,J=2.0Hz), 5.69(s, 2H). 180 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-MS[ES] 419.3(M+1)⁺. methyl-1H-pyrrol-2-yl)-1H-[1,2,3]triazole-4-carboxylic acid 1811-(3,5-Bis-trifluoromethyl-benzyl)-5- ¹H NMR(400MHz, DMSO) δ 9.05(d,pyrazin-2-yl-1H-[1,2,3]triazole-4- 1H, J=1.6), 8.67(m, 2H), 8.04(s, 1H),carboxylic acid 7.86(s, 2H), 5.86(s, 2H). 1821-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 418.1(M+1)⁺pyrimidin-5-yl-1H-[1,2,3]triazole-4- carboxylic acid 1831-(3,5-Bis-trifluoromethyl-benzyl)-5-(4- MS(ES) 462.1(M+1)⁺methylsulfanyl-phenyl)-1H- [1,2,3]triazole-4-carboxylic acid 1841-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES−) 415.0(M−1)⁻. ¹HNMR(400MHz, pyridin-2-yl-1H-[1,2,3]triazole-4- DMSO-d₆) δ 13.2(br s,1H), carboxylic acid 8.70(m, 1H), 8.05(s, 1H), 7.93(dt, 1H, J=2.0,7.8Hz), 7.83(s, 2H), 7.74(m, 1H), 7.53(ddd, 1H, J=1.0, 4.9, 7.3Hz),5.88(s, 2H). 185 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−)415.1(M−1)⁻; ¹H NMR(400MHz, pyridin-3-yl-1H-[1,2,3]triazole-4- DMSO-d6)δ 13.05(br s, 1H), carboxylic acid 8.66(m, 1H), 8.56(d, 1H, J=1.5Hz),8.05(s, 1H), 7.85(dt, 1H, J=2.0, 7.8Hz), 7.71(s, 2H), 7.48(dd, 1H,J=4.9, 7.8Hz), 5.79(s, 2H). 186 1-(3,5-Bis-trifluoromethyl-benzyl)-5-MS(ES) 417.1(M+1)⁺; ¹H NMR(400MHz, pyridin-4-yl-1H-[1,2,3]triazole-4-DMSO-d6) δ 13.17(br s, 1H), carboxylic acid 8.67(br s, 2H), 8.04(s, 1H),7.73(s, 2H), 7.45(d, 2H, J=5.4Hz), 5.78(s, 2H). 1871-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 416.4(M−1)⁻; ¹HNMR(400MHz, pyridazin-4-yl-1H-[1,2,3]triazole-4- DMSO-d6) δ 13.28(br s,1H), carboxylic acid 9.39(dd, 1H, J=0.9, 5.4Hz), 9.30(dd, 1H, J=1.0,2.5Hz), 8.07(s, 1H), 7.88(dd, 1H, J=2.4, 5.3Hz), 7.83(s, 2H), 5.81(s,2H). 188 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 404.3(M−1)⁻. ¹HNMR(400MHz, furan-2-yl-1H-[1,2,3]triazole-4-carboxylic DMSO-d6) δ13.27(br s, 1H), acid 8.09(s, 1H), 7.92(d, 1H, J=1.5Hz), 7.86(s, 2H),7.28(d, 1H, J=3.4Hz), 6.70(dd, 1H, J=2.0, 3.4Hz), 6.04(s, 2H). 1891-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 404.2(M−1)⁻; ¹HNMR(400MHz, furan-3-yl-1H-[1,2,3]triazole-4-carboxylic DMSO-d6) δ13.05(br s, 1H), acid 8.08(m, 2H), 7.83(m, 1H), 7.78(s, 2H), 6.71(dd,1H, J=1.0, 2.0Hz), 5.87(s, 2H). 1901-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES−) 420.0(M−1)⁻; ¹HNMR(400MHz, thiophen-2-yl-1H-[1,2,3]triazole-4- DMSO-d6) δ 13.14(br s,1H), carboxylic acid 8.06(s, 1H), 7.85(dd, 1H, J=1.0, 4.9Hz), 7.69(s,2H), 7.40(dd, 1H, J=1.5, 3.4Hz), 7.20(dd, 1H, J=3.4, 4.9Hz), 5.84(s,2H). 191 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(5- MS(ES−) 434.0(M−1)⁻;¹H NMR(400MHz, methyl-thiophen-2-yl)-1H-[1,2,3]triazole- DMSO-d6) δ13.13(br s, 1H), 4-carboxylic acid 8.01(s, 1H), 7.69(s, 2H), 7.18(d, 1H,J=3.4Hz), 6.90(dd, 1H, J=1.0, 3.4Hz), 5.83(s, 2H), 2.45(d, 3H, J=1.0Hz).192 1-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES) 418.1(M+1)⁺;pyrazin-2-yl-1H-[1,2,3]triazole-4- carboxylic acid 1931-(3,5-bis-trifluoromethyl-benzyl)-5-(4- MS(ES) 434.0(M+1)⁺;fluoro-phenyl)-1H-[1,2,3]triazole-4- carboxylic acid 1945-Amino-1-(3,5-bis-trifluoromethyl- MS(ES) 355.2(M+1)⁺; ¹H NMR(400MHz,benzyl)-1H-[1,2,3]triazole-4-carboxylic DMSO-d6) δ 12.51(s, COOH), acid8.09(s, 1H), 7.90(s, 2H), 6.34(s, 2H), 5.61(s, 2H). 1951-(3,5-Bis-trifluoromethyl-benzyl)-5- ¹H NMR(400MHz, DMSO-d6) δisopropyl-1H-[1,2,3]triazole-4-carboxylic 13.08(br s, 1H), 8.14(s, 1H),7.88(s, 2H), acid 5.96(s, 2H), 3.52(quint., 1H, J=7.3), 1.19(d, 6H,J=7.0)

Preparation 1961-(3,5-Bis-trifluoromethyl-benzyl)-5-butoxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (120 mg, 0.31 mmol) in DMF (5.0 mL) with 1-iodobutane(40 μL) and cesium flouride (188 mg, 1.24 mmol) and stir at RT. After 3h., add cesium carbonate (200 mg). After 16 h., add H₂O (5 mL), stir thesolution for 15 min, then extract with ether (3'10 mL). Combine theorganic layers and wash with H₂O (10 mL) and brine (10 mL) then dry,filter, and concentrate. Purify the crude material by chromatography onsilica gel using 20% EtOAc/bexanes to afford the title compound as aclear, colorless oil. MS(ES) 440.1 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃) δ7.84(s, 1H), 7.75 (s, 2H), 5.44 (s, 2H), 4.51 (t, 2H, J=6.6 Hz), 4.40 (t,2H, J=7.0 Hz), 1.63 (m, 2H), 1.40 (t, 3H, J=7.0 Hz), 1.33 (m, 2H), 0.88(t, 3H, J=7.4 Hz).

Using a method analogous to Preparation 196, with the appropriatestarting materials, the following compounds may be prepared. Prep.#Product Data 197 5-Benzyloxy-1-(3,5-bis-trifluoromethyl- MS(ES)474.1(M+1)⁺; ¹H NMR(400MHz, benzyl)-1H-[1,2,3]triazole-4-carboxylicCHCl₃) δ 7.80(s, 1H), 7.56(s, acid ethyl ester 2H), 7.17-7.31(m, 5H),5.54(s, 2H), 5.23(s, 2H), 4.45(q, 2H, J=7.0Hz), 1.40(t, 3H, J=7.0Hz).198 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 412.1(M+1)⁺; ¹HNMR(400MHz, ethoxy-1H-[1,2,3]triazole-4-carboxylic CHCl₃) δ 7.85(s, 1H),7.77(s, acid ethyl ester 2H), 5.46(s, 2H), 4.59(q, 2H, J=7.5Hz), 4.40(q,2H, J=7.5Hz), 1.41(t, 3H, J=7.5Hz), 1.31(t, 3H, J=7.5Hz). 1991-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 426.0(M+1)⁺; ¹H NMR(400MHz,propoxy-1H-[1,2,3]triazole-4-carboxylic CHCl₃) δ 7.83(s, 1H), 7.75(s,acid ethyl ester 2H), 5.46(s, 2H), 4.47(t, 2H, J=6.6Hz), 4.38(q, 2H,J=7.1Hz), 1.70(s, 2H, J=7.1Hz), 1.39(t, 3H, J=6.6Hz), 0.92(t, 3H,J=7.1Hz).

Preparation 2001-(3,5-Bis-trifluoromethyl-benzyl)-5-methoxy-1H-[1,2,3]triazole-4-carboxylicacid

Add dimethyl sulphate (0.14 g, 1.15 mmol) to a suspension of1-(3,5-bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (0.21 g, 0.55 mmol) and potassium carbonate (0.40 g,1.23 mmol) in DMF (2.0 mL) and stir at 60° C. After 18 h., dilute withwater and extract with EtOAc. Combine the organic layers and wash withwater and brine, then dry, filter, and concentrate to give crude1-(3,5-bis-trifluoromethyl-benzyl)-5-methoxy-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (0.22 g, 95%). Dissolve this material in 1:1dioxane:water (6.0 mL), add lithium hydroxide monohydrate (0.14 g, 3.34mmol) and stir the mixture at RT. After 3 h, dilute with water andneutralize to pH 7 with 1N aqueous HCl. Collect the white precipitate byfiltration and dry under reduced pressure to give the title compound inquantitative yield as a white solid. MS(ES) 370.1 (M+1)⁺; ¹H NMR (400MHz, d₆-DMSO) δ8.10 (s, 1H), 8.04 (s, 2H), 5.45 (s, 2H), 4.19 (s, 3H).

Preparation 201 3,5-dichlorobenzylazide

Dissolve 3,5-dichlorobenzyl alcohol (10.0 g, 56.0 mmol) in DMF (20 mL)and slowly add thionyl chloride (4.40 mL, 60.0 mmol) to the mixture,while cooling in a water bath. After stirring for 1 h, add K₂CO₃ (15.8g, 110 mmol) and stir an additional 1 h. Then add DMSO (50 mL) andsodium azide (5.60 g, 86 mmol) and stir the mixture overnight at RT.Dilute the mixture with water and extract with EtOAc. Wash the combinedextracts with water and dry over Na₂SO₄. Concentrate to give the titlecompound (10.11 g, 89%) as an oil. Use without further purification.MS(ES) 201.0 (M+1)⁺.

Preparation 2021-(3,5-Dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

Combine diethylmalonate (1.91 g, 11.9 mmol), 3,5-dichlorobenzylazide(2.40 mL, 11.9 mmol), and potassuim carbonate (4.94 g, 35.8 mmol) inDMSO (15 mL) and heat the mixture for 8 h at 50° C. Cool the mixture toRT and dilute with water. Adjust the pH to 5-6 with 1N HCl, and extractwith CH₂Cl₂. Wash the combined extracts with water, dry over Na₂SO₄ andconcentrate in vacuo. Purify the residue by chromatography over silicagel using a CH₂Cl₂/MeOH gradient to provide 3.28 g of impure product asan oil. Use without further purification. MS(ES) 316.0 (M+1)⁺.

Preparation 2035-Chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acidethyl ester

Combine1-(3,5-dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acidethyl ester (3.25 g, 10.3 mmol) with PCl₅ (4.29 g, 20.6 mmol) in toluene(75 mL) and heat at 40-50° C. After 4 h., cool to RT and concentrate thereaction mixture. Add aqueous NaHCO₃ and extract with Et₂O. Dry thecombined extracts over Na₂SO₄ and concentrate in vacuo. Purify theresidue by chromatography over silica gel using CH₂Cl₂ to provide thetitle compound (1.83 g) as an impure oil. Use without furtherpurification. MS(ES) 334.0 (M+1)⁺.

Preparation 2045-chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(2-chloro-benzyl)-isopropyl-amide

Combine (2-chloro-benzyl)-isopropyl-amine (240 mg, 1.31 mmol) with5-chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(400 mg, 1.31 mmol), EDCI (250 mg, 1.30 mmol), HOAt (178 mg, 1.31 mmol),and DIEA (0.20 mL, 1.15 mmol), in DMF (8 mL) and stir the mixture at RT.After 72 h, concentrate the mixture, then dissolve the residue in EtOAcand wash with water. Dry the organic layer over sodium sulfate, filter,and concentrate in vacuo. Purify the residue by chromatography oversilica gel using a MeOH/CH₂Cl₂ gradient to provide the title compound(103 mg, 17%) as a white solid. MS(ES) 471.0 (M+)⁺; R_(f)=0.19 (CH₂Cl₂).

Preparation 205 2-Methoxy-5-trifluoromethoxy-benzaldehyde

Combine 4-(trifluoromethoxy)anisole (10.0 g, 52.1 mmol) withhexamethylene tetramine (7.29 g, 52.1 mmol) in trifluoroacetic acid (50g) and heat the mixture overnight at 80° C. Cool the mixture to RT andconcentrate. Dissolve in Et₂O and wash with aqueous NaHCO₃ and brine.Dry over Na₂SO₄, filter and concentrate. Purify the residue bychromatography over silica gel to provide the title compound (3.49 g,30%) as a light yellow oil. MS(ES) 221.0 (M+1)⁺; R_(f)=0.69 (CH₂Cl₂).

Preparation 206 Isopropyl-(2-methoxy-5-trifluoromethoxy-benzyl)-amine

Combine 2-methoxy-5-trifluoromethoxy benzaldehyde (490 mg, 2.23 mmol)and isopropyl amine (197 mg, 3.34 mmol) in 1,2-dichloroethane (15 mL),add sodium triacetoxy-borohydride (945 mg, 4.46 mmol), and stir themixture overnight at RT. Quench the mixture with water and adjust pH to8.0 with 1N NaOH. Extract the mixture with dichloromethane, dry thecombined extracts over Na₂SO₄, filter and concentrate. Purify theresidue over silica gel using a CH₂Cl₂/MeOH gradient to provide thetitle compound (310 mg, 53%) as a light oil. MS(ES) 264.3 (M+1)⁺.

Preparation 207 (2-Methoxy-5-trifluoromethoxy-phenyl)-methanol

Dissolve 2-methoxy-5-trifluoromethoxy benzaldehyde (3.0 g, 13.6 mmol) inMeOH (50 mL) and add sodium borohydride (0.26 g, 6.88 mmol) and stir themixture at RT until reduction is complete. Concentrate the mixture anddissolve the residue in CH₂Cl₂. Wash with 1N NaOH, water, and brine, dryover sodium sulfate, filter, and concentrate. Purify the residue bychromatography over silica gel using a MeOH/CH₂Cl₂ gradient to providethe title compound (2.88 g, 95%) as a clear oil. MS(EI) 222.1 (M)⁺;R_(f)=0.28 (CH₂Cl₂).

Preparation 208 2-Azidomethyl-1-Methoxy-4-trifluoromethoxy-benzene

Dissolve (2-methoxy-5-trifluoromethoxy-phenyl)-methanol (2.8 g, 12.6mmol) in DMF (15 mL) and slowly add thionyl chloride (1.00 mL, 13.7mmol). Stir the mixture for 1 h at RT, then add K₂CO₃ (3.48 g, 25.2mmol) and stir the resulting mixture an additional 1 h. To this mixture,add sodium azide (1.23 g, 18.9 mmol) and DMSO (15 mL) and stir overnightat RT. Dilute the mixture with water and extract with EtOAc. Wash thecombined extracts with water, dry over sodium-sulfate, filter andconcentrate to give the title compound 2.14 g (69%) as an oil. MS(EI)247.1 (M)⁺.

Preparation 2091-(2-methoxy-5-trifluoromethoxy-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Combine ethyl isonicotinoyl acetate (2.13 g, 11.0 mmol),2-azidomethyl-1-methoxy-4-trifluoromethoxy-benzene (2.10 g, 8.5 mmol),and potassuim carbonate (4.7 g, 34.0 mmol) in DMSO (16 mL) and heat themixture at 50-60° C. After 72 h, cool the mixture to RT, dilute withwater, and extract with EtOAc. Dry the combined extracts over Na₂SO₄,filter, and concentrate. Purify the residue by chromatography oversilica gel using a CH₂Cl₂/MeOH gradient to provide the title compound(2.37 g, 38%) as a crystalline solid. MS(ES) 423.2 (M+1)⁺; Analysis forC₁₉H₁₇F₃N₄O₄: Calc'd: C, 54.03; H, 4.06; N, 13.27. Found: C, 54.13; H,4.16; N, 12.35.

Preparation 2101-(2-methoxy-5-trifluoromethoxy-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid

Combine1-(2-methoxy-5-trifluoromethoxy-benzyl)-5-pyridin-4-yl-1H-[[1,2,3]triazole-4-carboxylicacid ethyl ester (1.20 g, 2.84 mmol), 2N aqueous NaOH (8 mL), THF (2mL), and EtOH (2 mL) and stir at RT until hydrolysis is complete. Removethe organic solvents in vacuo and dilute the mixture with water. Adjustthe aqueous mixture to pH 3.0-4.0 with aqueous HCl and extract withCH₂Cl₂. Dry the combined extracts over Na₂SO₄, filter, and concentratein vacuo to give the title compound (1.08 g, 97%) as an off white solid.MS(ES−) 393.1 (M−1)⁻.

Preparation 2115-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid methyl ester

Combine 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (1.07 g, 3.98mmol), ethyl cyanoacetate (0.41 g, 3.63 mmol), and sodium methoxide (9.0mL, 0.5M solution in MeOH) in MeOH (4 mL) and stir at RT. After 48 h,concentrate the reaction mixture, add water and collect the precipitateby filtration and dry under reduced pressure to give the title compound(0.47 g, 34%) as a white solid. MS(ES) 369.2 (M+1)⁺; ¹H NMR (400 MHz,DMSO) δ8.10 (s, 1H), 7.90 (s, 2H), 6.75 (s, NH₂), 5.61 (s, 2H), 3.75 (s,3H).

Preparation 2121-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrrol-1-yl-1H-[1,2,3]triazole-4-carboxylicacid methyl ester

Add 2,5-dimethoxyfuran (80 mg, 0.61 mmol) slowly to a solution of5-amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid methyl ester (210 mg, 0.57 mmol) in glacial acetic acid (3 mL) andheat to reflux. After 2 h, cool to RT, dilute the reaction mixture withwater, and extract with EtOAc. Wash the EtOAc extract with water andbrine, then dry (Na₂SO4), filter, and concentrate to give the titlecompound in quantitative yield. Use without further purification. ¹H NMR(400 MHz, CDCl₃) δ7.83 (s, 1H), 7.47 (s, 2H), 6.64 (t, 2H, J=2.0 Hz),6.45 (t, 2H, J=2.0 Hz), 5.53 (s, 2H), 3.87 (s, 3H).

Preparation 213 3-(1-Methyl-]H-pyrrol-2-yl)-3-oxo-propionic acid ethylester

Add 1,1′-carbonyldiimidazole (2.6 g, 16.0 mmol) to a solution of1-methyl-1H-pyrrole-2-carboxylic acid (2.0 g, 16.0 mmol) in THF (20 mL)and stir at RT. After 12-24 h, add via cannula a preformed solution ofethyl hydrogen malonate (2.5 g, 19.3 mmol) and isopropyl magnesiumchloride (19.3 mL of 2M solution in THF) in THF (10 mL) at 0° C. Stir atRT for another 4 h, dilute with water, and extract with EtOAc. Wash theEtOAc extract with water and brine, then dry (Na₂SO₄), filter, andconcentrate. Purification by flash chromatography eluting with a lineargradient of 10% to 25% EtOAc in hexanes gives the title compound (1.2 g,38%). MS(ES−) 194.1 (M−1)⁻. ¹H NMR (400 MHz, CHCl₃) δ6.95 (dd, 1H, J=4.4Hz, 20), 6.84 (t, 1H, J=2.0 Hz), 6.13 (dd, 1H, J=4.4, 2.0 Hz), 4.19 (q,2H, J=7.2 Hz), 3.93 (s, 3H), 3.79 (s, 2H), 1.26 (t, 3H, J=7.2 Hz).

The following compound may be prepared using a method similar to theabove Preparation. Prep. # Product Data 2143-Oxo-3-pyrazin-2-yl-propionic MS(ES) 195.0(M+1)⁺ acid ethyl ester

Preparation 2151-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-methyl-1H-pyrrol-2-yl)-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester

Add 3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-propionic acid ethyl ester (1.0 g,5.1 mmol) and K₂CO₃ (2.8 g, 20.3 mmol) to a solution of1-azidomethyl-3,5-bis-trifluoromethyl-benzene (1.4 g, 5.2 mmol) in DMSO.Heat the mixture to 50° C. for 18 h, then cool to RT. Dilute thereaction mixture with water, acidify to pH 4 with 2N HCl, and extractwith EtOAc. Wash the EtOAc extract with water and brine, then dry(Na₂SO₄), filter, and concentrate. Purification by flash chromatographyeluting with a linear gradient of 15% to 30% EtOAc in hexanes gives thetitle compound (0.6 g, 40%). MS(ES) 447.0 (M+1)⁺; ¹H NMR (400 MHz,CHCl3) δ7.80 (s, 1H), 7.38 (s, 2H), 6.79 (dd, 1H, J=2.9, 1.9 Hz), 6.31(dd, 1H, J=3.9, 2.9 Hz), 6.25 (dd, 1H, J=3.9, 1.9 Hz), 5.61 (br s, 2H),4.35 (q, 2H, J=7.2 Hz), 3.00 (s, 3H), 1.31 (t, 3H, J=7.2 Hz).

Using a method similar to the above Preparation, with the appropriatestarting materials, the following compounds may be prepared andisolated. Prep. # Product Data 2161-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrazin- MS(ES) 446.1(M+1)⁺2-yl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester 2171-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 446.2(M+1)⁺pyrimidin-5-yl-1H-[1,2,3]triazole-4- carboxylic acid ethyl ester 2181-(3,5-Bis-trifluoromethyl-benzyl)-5-(4- MS(ES) 476.1(M+1)⁺methylsulfanyl-phenyl)-1H-[1,2,3]triazole-4- carboxylic acid methylester 219 1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin- MS(ES)431.1(M+1)⁺; ¹H 3-yl-1H-[1,2,3]triazole-4-carboxylic acid NMR(400MHz,CDCl₃) δ 8.76(s, 1H), methyl ester 8.49(s, 1H), 7.79(s, 1H), 7.51(m,1H), 7.41(s, 2H), 7.40(m, 1H), 5.59(s, 2H), 3.83(s, 3H). 2201-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin- MS(ES) 445.2(M+1)⁺; ¹H4-yl-1H-[1,2,3]triazole-4-carboxylic acid NMR(400MHz, CDCl₃) δ 8.74(dd,2H, J=1.5, ethyl ester 4.4Hz), 7.80(s, 1H), 7.45(s, 2H), 7.13(dd, 2H,J=2.0, 4.4Hz), 5.56(s, 2H), 4.27(q, 2H, J=7.3Hz), 1.28(t, 3H, J=7.3Hz).221 1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 446.2(M+1)⁺; ¹Hpyridazin-4-yl-1H-[1,2,3]triazole-4-carboxylic NMR(400MHz, CDCl₃) δ9.27(dd, 1H, J=0.9, acid ethyl ester 5.4Hz), 9.07(m, 1H), 7.81(s, 1H),7.55(s, 2H), 7.39(dd, 1H, J=2.4, 5.4Hz), 5.68(s, 2H), 4.25(q, 2H,J=7.3Hz), 1.29(t, 3H, J=7.3Hz). 2221-(3,5-Bis-trifluoromethyl-benzyl)-5-furan-2- MS(ES) 434.2(M+1)⁺; ¹Hyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl NMR(400MHz, CDCl₃) δ7.76(s, 1H), ester 7.64(s, 2H), 7.57(m, 1H), 7.44(d, 1H, J=3.4Hz),6.56(dd, 1H, J=2.0, 3.4Hz), 5.94(s, 2H), 4.40(q, 2H, J=7.3Hz), 1.38(t,3H, J=7.3Hz). 223 1-(3,5-Bis-trifluoromethyl-benzyl)-5-furan-3- MS(ES)434.1(M+1)⁺; ¹H yl-1H-[1,2,3]triazole-4-carboxylic acid ethylNMR(400MHz, CDCl₃) δ 7.81(s, 1H), ester 7.64(s, 1H), 7.55(m, 3H), 6.41(m1H), 5.65(s, 2H), 4.36(q, 2H, J=7.3Hz), 1.34(t, 3H, J=7.3Hz). 2241-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(es) 450.0(M+1)⁺; ¹Hthiophen-2-yl-1H-[1,2,3]triazole-4-carboxylic NMR(400MHz, CDCl₃) δ7.77(s, 1H), acid ethyl ester 7.58(dd, 1H, J=1.0, 4.9Hz), 7.47(s, 2H),7.14(dd, 1H, J=3.4, 4.9Hz), 7.10(dd, 1H, J=1.0, 3.4Hz), 5.63(s, 2H),4.30(q, 2H, J=7.3Hz), 1.26(t, 3H, J=7.3Hz). 2251-(3,5-Bis-trifluoromethyl-benzyl)-5-(5- MS(ES) 464.0(M+1)⁺; ¹Hmethyl-thiophen-2-yl)-1H-[1,2,3]triazole-4- NMR(400MHz, CDCl₃) δ 7.80(s,1H), carboxylic acid ethyl ester 7.49(s, 2H), 6.90(d, 1H, J=3.9Hz),6.80(m, 1H), 5.64(s, 2H), 4.34(q, 2H, J=7.3Hz), 2.51(d, 3H, J=1.0Hz),1.32(t, 3H, J=7.3Hz). 226 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrazin-MS(ES) 431.3(M+1)⁺; 2-yl-1H-[1,2,3]triazole-4-carboxylic acidR_(f)=0.29(1:1 EtOAc/hexanes). methyl ester 2271-(3,5-Bis-trifluoromethyl-benzyl)-5- ¹H NMR(400MHz, CDCl₃) δisopropyl-1H-[1,2,3]triazole-4-carboxylic acid 7.85(s, 1H), 7.57(s, 2H),5.71(s, 2H), ethyl ester 4.43(quart., 2H, J=6.8), 3.33(quint., 1H,J=7.1), 1.43(t, 3H, J=6.9), 1.25(d, 6H, J=6.6)

Preparation 228 Pyrimidine-5-carboxylic acid methoxy-methyl-amide

Combine EDCI (0.99 g, 5.18 mmol) with a solution of O,N-hydroxylaminehydrochloride (0.51 g, 5.23 mmol), pyrimidine-5-carboxylic (540 mg, 4.35mmol), triethylamine (1.5 mL, 10.4 mmol), and DMAP (0.64 g, 5.24 mmol)in DMF (10 mL) and stir at RT. After 24 h, treat the reaction mixturewith saturated NaHCO₃ and extract with CH₂Cl₂. Wash the organic layerwith water, dry over sodium sulfate, filter, and concentrate underreduced pressure. Purification by flash chromatography eluting with alinear gradient of 15% to 30% EtOAc in hexanes gives the title compound(0.15 g, 21%). MS(ES) 168.2 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃) δ9.21 (s,1H), 9.02 (s, 2H), 3.53 (s, 3H), 3.34 (s, 3H).

Using a method similar to the above Preparation, with the appropriatecarboxylic acid starting material, the following compounds may beprepared and isolated. Prep. # Product Data 229 Pyridazine-4-carboxylicacid MS(ES) 168.2(M+1)⁺; ¹H NMR(400MHz, methoxy-methyl-amide CDCl₃) δ9.43(m, 1H), 9.32(m, 1H), 7.73(m, 1H), 3.55(s, 3H), 3.38(s, 3H). 230Thiophene-2-carboxylic acid MS(ES) 172.0(M+1)⁺. ¹H NMR(400MHz,methoxy-methyl-amide CDCl₃) δ 7.94(dd, 1H, J=1.5, 3.4Hz), 7.53(dd, 1H,J=1.0, 4.9Hz), 7.08(dd, 1H, J=3.4, 4.9Hz), 3.76(s, 3H), 3.35(s, 3H). 2315-Methyl-thiophene-2-carboxylic MS(ES) 186.0(M+1)⁺. ¹H NMR(400MHz, acidmethoxy-methyl-amide CDCl₃) δ 7.76(d, 1H, J=3.4Hz), 6.76(m, 1H), 3.74(s,3H), 3.32(s, 3H), 2.49(d, 3H, J=1.0Hz).

Preparation 232 3-oxo-3-pyrimidin-5-yl-propionic acid ethyl ester

Add n-BuLi (1.12 mL of 1.6M solution in hexane, 1.8 mmol) slowly to asolution of diisopropylamine (0.25 mL, 1.8 mmol) in THF (5 mL) at −78°C. Stir 5 min, then add a solution of EtOAc (0.16 mL, 1.8 mmol) in THF(5 mL). Stir at −78° C. for 25 min, then add pyrimidine-5-carboxylicacid methoxy-methyl-amide (0.14 g, 0.9 mmol). After another 3 h, treatthe reaction mixture with 1N HCl solution (25 mL) and extract withEtOAc. Wash the organic extract with water, dry (Na2SO₄), filter, andconcentrate under reduced pressure to provide the title compound. Usewithout further purification. MS(ES) 195.1 (M+1)⁺; ¹H NMR (400 MHz,CDCl₃) δ9.21 (s, 1H), 9.02 (s, 2H), 4.24 (q, 2H, J=7.3 Hz), 3.94 (s,2H), 1.29 (t, 3H, J=7.3 Hz).

Using a method similar to the above Preparation, with the appropriateamide starting material, the following compounds may be prepared andisolated. Prep. # Product Data 233 3-Oxo-3-pyridazin-4- MS(ES)195.2(M+1)⁺; ¹H NMR(400MHz, CDCl₃) δ yl-propionic acid ethyl 12.43(m,1H), 9.45(m, 1H), 9.31(d, 1H, J=5.4Hz), ester 7.78(m, 1H), 5.85(m, 1H),4.29(dq, 2H, J=1.5, 7.5Hz), 1.34(dt, 3H, J=1.5, 7.4Hz). 2343-Oxo-3-thiophen-2- MS(ES) 199.0(M+1)⁺; ¹H NMR(400MHz, CDCl₃) δyl-propionic acid ethyl 7.72(m, 1H), 7.68(m, 1H), 7.13(m, 1H), 4.19(q,2H, J=7.3Hz), ester 3.90(s, 2H), 1.24(t, 3H, J=7.3Hz). 2353-(5-Methyl-thiophen- MS(ES−) 211.2(M−1)⁻; ¹H NMR(400MHz, CDCl₃) δ2-yl)-3-oxo-propionic 7.53(d, 1H, J=3.4Hz), 6.79(dq, 1H, J=1.0, 3.9Hz),4.18(q, acid ethyl ester 2H, J=7.3Hz), 3.83(s, 2H), 2.52(d, 3H,J=1.0Hz), 1.24(t, 3H, J=7.3Hz).

Preparation 236 3-(4-Methylsulfanyl-phenyl)-3-oxo-propionic acid methylester

Add 1-(4-methylsulfanyl-phenyl)-ethanone (0.50 g, 3.0 mmol) to asuspension of sodium hydride (0.14 g, 3.1 mmol) in THF (20 mL) and stirthe mixture at RT. After 1 h, add dimethyl carbonate (0.64 g, 7.1 mmol)and warm to reflux. After 18 h, dilute the reaction mixture with water,add acetic acid to until the pH=6, then extract with EtOAc. Combine theorganic layers and wash with water, and brine, dry over sodium sulfate,filter, and concentrate under reduced pressure. Purification by flashchromatography eluting with a linear gradient of 15% to 35% EtOAc inhexanes gives the title compound (0.60 g, 90%) as a mixture oftautomers. MS(ES) 225.1 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃) δ7.85 (dd, 2H,J=8.9 Hz), 7.28 (dd, 2H, J=8.9 Hz), 3.96 (s, 2H), 3.75 (s, 3H), 2.52 (s,3H).

Preparation 237 1-(2-chloro-phenyl)-pyrazolidine hydrochloride

Dissolve 2-(2-chloro-phenyl)-pyrazolidine-1-carboxylic acid tert-butylester (50 mg, 1 eq) in a solution of acetic acid saturated with HCl (6mL) and stir at RT. After 6 h, concentrate the mixture to dryness underreduced pressure to give the title compound. MS(IS) 183.0 (M+1)⁺;Analysis calc'd for C₉H₁₁ClN₂.HCl: C, 49.33; H, 5.52; N, 12.79. Found:C, 49.28; H, 5.57; N, 12.70.

Using a method similar to Preparation 237, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Prep. #Product Data 238 2-(2-chloro-4-trifluoromethyl-phenyl)- MS(ES)251.0(M+1)⁺; Anal. pyrazolidine hydrochloride calc'd forC₁₀H₁₀ClF₃N₂.HCl: C, 41.83; H, 3.86; N, 9.75. Found: C, 41.45; H, 3.67;N, 9.48. 239 2-(2,4-difluoro-phenyl)-pyrazolidine MS(ES) 185.1(M+1)⁺.hydrochloride 240 2-(2-chloro-phenyl)-tetrahydro-pyridazine MS(ES)197.0(M+1)⁺. hydrochloride

Preparation 241 2-(2-chloro-phenyl)-pyrazolidine-1-carboxylic acidtert-butyl ester

Dissolve NaH (33 mg, 2.0 eq.) and 1, 3-dibromopropane (0.04 mL, 1.0 eq.)in DMF at 0° C. Add N′-(2-chloro-phenyl)-hydrazinecarboxylic acidtert-butyl ester (0.1 g, 1.0 eq.) and stir at 0° C. After 1 h, quenchthe reaction with water and concentrate the mixture in vacuo. Dissolvethe residue in 20% iPrOH/CHCl₃ and wash with water, saturated aqueousNaHCO₃, and brine. Dry the organic layer over Na₂SO₄, filter, andconcentrate. Purify the residue by chromatography on silica gel toprovide the title compound. MS(ES) 283.1 (M+1)⁺; R_(f)=0.81 (1:1EtOAc/hexanes).

Using a method similar to Preparation 241, with the appropriate startingmaterials, owing compounds may be prepared and isolated. Prep. # ProductData 242 2-(2-chloro-4-trifluoromethyl-phenyl)- MS(ES) 351.1(M+1)⁺;pyrazolidine-1-carboxylic acid tert-butyl R_(f)=0.50(30% esterEtOAc/hexanes) 243 2-(2,4-difluoro-phenyl)-pyrazolidine-1- MS(ES)285(M+1)⁺; carboxylic acid tert-butyl ester R_(f)=0.76(1:1EtOAc/hexanes)

Preparation 244 N′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butylester

Dissolve 2-chlorophenylhydrazine hydrochloride (5.0 g, 1.0 eq.) in H₂O(50 mL) and THF (50 mL). Add K₂CO₃ (11.6 g, 3.0 eq) anddi-t-butyl-dicarbonate (6.1 g) and stir at RT. After 72 h, concentratethe mixture in vacuo. Dissolve the residue in 20% iPrOH/CHCl₃ and washwith water, saturated aqueous NaHCO₃, and brine. Dry the organic layerover Na₂SO₄, filter, and concentrate. Purify the residue bychromatography over silica gel to provide the title compound. MS(ES−)241.0 (M−1)⁻; R_(f)=0.13 (10% EtOAc/hexanes).

Using a method similar to Preparation 244, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Prep. #Product Data 245 N′-(2-chloro-4-trifluoromethyl-phenyl)- MS(ES−)309.1(M−1)⁻; hydrazinecarboxylic acid tert-butyl ester R_(f)=0.38(20%EtOAc/hexanes) 246 N′-(2,4-difluoro-phenyl)- MS(ES−) 243.1(M−1)⁻;hydrazinecarboxylic acid tert-butyl ester R_(f)=0.62(30% EtOAc/hexanes)

Preparation 247 3-Oxo-3-pyrazin-2-yl-propionic acid methyl ester

In a dropwise fashion, add 2-pyrazine methylester (1.0 g, 1.0 eq.) andmethyl acetate (1.14 mL, 2.0 eq.) as a solution in toluene (10 mL) to ahot (90° C.) mixture of sodium methoxide (600 mg, 1.5 eq.) in toluene(100 mL). Heat the mixture for 20 h. at 90° C., then cool to RT andconcentrate in vacuo. Dissolve the residue in excess methyl acetate,heat at reflux for another 20 h. Cool the mixture to RT, add H₂O, andextract with EtOAc. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to give the title compound that was used withoutfurther purification. R_(f)=0.58 (1:1 EtOAc/hexanes).

Preparation 248 2-(2-chloro-phenyl)-tetrahydro-pyridazine-1-carboxylicacid tert-butyl ester

Dissolve NaH (0.17 g, 2.0 eq.) and 1,4-dibromobutane (0.24 mL, 1.0 eq.)in DMF (10 mL) and cool to 0° C. AddN′-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (1.0 g,1.0 eq.) and stir the mixture for 1 h. at 0° C., then quench with H₂Oand concentrate in vacuo. Dissolve the residue in 20% iPrOH/CHCl₃, washwith water, saturated aqueous NaHCO₃, and brine, then dry (Na₂SO₄),filter, and concentrate. Purify the residue by chromatography on silicagel to provide the title compound. MS(ES) 297.1 (M+1)⁺; R_(f)=0.68 (30%EtOAc/hexanes).

Preparation 249 8-chloro-1,2,3,4-tetrahydro-quinoline

Dissolve 8-chloroquinoline (10.0 g, 1.0 eq.) in HOAc (100 mL), add PtO₂(1.0 g) and shake under hydrogen (45 psi) at RT. After 4 h, removehydrogen, filter off the catalyst, and concentrate in vacuo. Dissolvethe residue in THF, and slurry with polyvinylpyridine, then filter andconcentrate in vacuo. Purify the residue by chromatography on silica gelto provide the title compound. MS(ES) 168.0 (M+1)⁺; R_(f)=5%EtOAc/hexanes).

Preparation 250 (2,4-dichloro-phenyl)-isopropyl-amine

Combine 2,4-dichloroaniline (800 mg, 5.0 mmol) and 2-bromopropane (0.47mL, 5.0 mmol) neat in a sealed tube and heat at 100° C. After 16 h, coolto RT, add CHCl₃ and wash with saturated aqueous NaHCO₃, and brine, dryover sodium sulfate, filter, and concentrate. Purify by columnchromatography using an EtOAc/hexanes gradient to afford 553 mg (35%) ofthe title compound as colorless oil. MS(ES) 204.0 (M+1)⁺; R_(f)=0.71(10% EtOAc/hexanes).

Using a method similar to Preparation 250, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Prep. #Product Data 251 (2-chloro-4-fluoro-phenyl)-isopropyl- MS(ES)188.0(M+1)⁺; R_(f)=0.75(10% amine EtOAc/hexanes). 252(2-chloro-4-trifluoromethyl-phenyl)- R_(f)=0.75(5% EtOAc/hexanes)isopropyl-amine 253 (3,4-difluorophenyl)-isopropyl-amine MS(ES)172.1(M+1)⁺; R_(f)=0.36 (10% EtOAc/hexanes). 254(2,4-dichloro-benzyl)-isopropyl-amine MS(ES) 218.1(M+1)⁺; R_(f)=0.4(1:1EtOAc/hexanes) 255 (3,4-difluoro-benzyl)-isopropyl-amine MS(ES)196.1(M+1)⁺; R_(f)=0.15(10% MeOH/CHCl₃). 256(2-chloro-benzyl)-isopropyl-amine MS(ES) 184.1(M+1)⁺; R_(f)=0.08(1:1EtOAc/hexanes) 257 (2-chloro-4-fluoro-benzyl)-isopropyl- MS(ES)202.0(M+1)⁺; R_(f)=0.23(1:1 amine EtOAc/hexanes). 258(R)-[1-(2-chloro-phenyl)-ethyl]-isopropyl- MS(ES) 198(M+1)⁺;R_(f)=0.32(5% amine MeOH/CHCl₃). 259 (2-Chloro-phenyl)-isopropyl-amineMS(ES) 170.2(M+1)⁺; R_(f)=0.71(25% EtOAc/hexanes).

Preparation 260 (2-chloro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine

Combine 2-chloroaniline (0.41 mL, 3.9 mmol) and1-(2-chloroethyl)pyrrolidine hydrochloride (670 mg, 3.9 mmol) in asealed tube and heat at 100° C. After 16 h, add CHCl₃ and wash withsaturated aqueous NaHCO₃ and brine, dry over Na₂SO₄, filter, andconcentrate. Purify the residue via radial chromatography using aMeOH/CHCl₃ gradient to afford 384 mg (44%) of the title compound as tanoil. MS(ES) 225.1 (M+1)⁺; R_(f)=0.24 (10% MeOH/CHCl₃).

Using a method similar to Preparation 260, with the appropriate startingmaterials, owing compounds may be prepared and isolated. Prep. # ProductData 261 N′-(2-chloro-phenyl)-N,N-dimethyl-ethane- MS(ES) 199.1(M+1)⁺;1,2-diamine R_(f)=0.25(10% MeOH/CHCl₃). 262(2-chloro-phenyl)-(2-piperidin-1-yl-ethyl)- MS(ES) 239.1(M+1)⁺; amineR_(f)=0.42(10% MeOH/CHCl₃). 263(2-chloro-phenyl)-(2-morpholin-4-yl-ethyl)- MS(ES) 241.1(M+1)⁺; amineR_(f)=0.50(80% EtOAc/hexanes). 264(2-chloro-4-fluoro-phenyl)-(2-pyrrolidin-1-yl- MS(ES) 243.1(M+1)⁺;ethyl)-amine R_(f)=0.23(10% MeOH/CHCl₃). 265N′-(2-chloro-4-fluoro-phenyl)-N,N-dimethyl- MS(ES) 217.1(M+1)⁺;ethane-1-diamine R_(f)=0.17(10% MeOH/CHCl₃). 266(2-chloro-4-fluoro-phenyl)-(2-morpholin-4-yl- MS(ES) 259.0(M+1)+;ethyl)-amine R_(f)=0.40(80% EtOAc/hexanes). 267(2-chloro-4-fluoro-phenyl)-(2-piperidin-1-yl- MS(ES) 257.1(M+1)+;ethyl)-amine R_(f)=0.33(10% MeOH/CHCl₃). 268N′-(2,4-dichloro-phenyl)-N,N-dimethyl- MS(ES) 233.0(M+1)⁺;ethane-1,2-diamine R_(f)=0.20(10% MeOH/CHCl₃). 269(2,4-dichloro-phenyl)-(2-pyrrolidin-1-yl- MS(ES) 259.0(M+1)⁺;ethyl)-amine R_(f)=0.16(10% MeOH/CHCl₃). 270(2-chloro-phenyl)-(2-trimethylsilanyloxy- MS(ES) 244.1(M+1)⁺;ethyl)-amine R_(f)=0.80(20% EtOAc/hexanes). 271(R)-[1-(2-chloro-phenyl)-ethyl]-(2-pyrrolidin- MS(ES) 253.1(M+1)⁺;1-yl-ethyl)-amine R_(f)=0.10(10% MeOH/CHCl₃). 272(2-chloro-benzyl)-(2-methoxy-ethyl)-amine MS(ES) 201.9(M+1)⁺;R_(f)=0.36(10% MeOH/CHCl₃).

Preparation 273(R,S)-{2-[1-(2-chloro-phenyl)-ethylamino]-ethyl}-carbamic acidtert-butyl ester

Add N-(2-aminoethyl)carbamic acid t-butyl ester (10.0 g, 62.0 mmol) to asolution of 2′-chloroacetophenone (11.5 mL, 74.4 mmol) in MeOH (80 mL).Add sodium cyanoborohydride (11.7 g, 186.0 mmol) and acetic acid (5drops) and stir at RT. After 16 h, quench with H₂O and concentrate themixture to dryness. Dissolve in 20% iPrOH/CHCl₃ and wash with saturatedaqueous NaHCO₃ and brine, dry over Na₂SO₄, filter, and concentrate.Purify the residue by column chromatography using an EtOAc/hexanesgradient to yield 5.5 g (30%) of the title compound as colorless oil,which solidifies upon standing. MS(ES) 299.1 (M+1)⁺; R_(f)=0.34 (1:1EtOAc/hexanes).

Using a method similar to Preparation 273, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Prep. #Product Data 274 [2-(2-Chloro-benzylamino)- MS(ES) 287.1(M+1)⁺;ethyl]-carbamic acid R_(f)=0.28(1:1 EtOAc/hexanes). tert-butyl ester 275[2-(2-chloro-4-fluoro- MS(ES) 303.1(M+1)⁺; benzylamino)-ethyl]-carbamicR_(f)=0.21(1:1 EtOAc/hexanes). acid tert-butyl ester 276(2-Chloro-benzyl)-pyridin- MS(ES) 232.9(M+1)⁺; 4-yl-methyl-amineR_(f)=0.20(80% EtOAc/hexanes).

Preparation 277 2-chloro-N-methyl-benzenesulfonamide

Combine 2-chlorobenzenesulfonyl chloride (5.0 g, 1.0 eq.) andN-methylamine (25 mL of a 2N solution in THF, 2.0 eq.) in a sealed tubewith THF (25 mL) and stir at RT. After 16 h, concentrate the mixture invacuo. Dissolve the residue in 20% iPrOH/CHCl₃, and wash with saturatedaqueous NaHCO₃ and brine. Dry the organic layer over Na₂SO₄, filter, andconcentrate. Purify the residue by chromatography to give the titlecompound (94% yield). MS(ES) 205.0 (M+1)⁺; R_(f)=0.70 (1:1EtOAc/hexanes).

Preparation 278 2-chloro-N-methyl-benzamide

Combine 2-chlorobenzoic acid, (10.0 g, 1 eq), N-methylamine (70 mL of a2N soln in THF, 1.5 eq.), EDCI (12.2 g, 1.1 eq.), HOAt (8.7 g, 1.1 eq.),TEA (10.0 mL, 1.1 eq.) and DMAP (5 mg) in DMF (50 mL) and stir overnightat RT. Concentrate the mixture to dryness and dissolve in 20%iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃ and brine. Dry (Na2SO4),filter, and concentrate to dryness. Purify the residue by chromatographyto provide the title compound (76% yield). MS(ES) 554.9 (M+1)⁺;R_(f)=0.60 (1:1 EtOAc/hexanes).

Preparation 279 3-methyl-but-2-enoic acid N′-(2-chloro-phenyl)-hydrazide

Dissolve sodium metal (1.5 g, 2.3 eq) in n-butanol (25 mL), then add2-chlorophenylhydrazine hydrochloride (5.0 g, 1.0 eq.) and stir 15 min.Add methyl,3,3-dimethylacrylate (3.8 mL, 1.5 eq.) dropwise, then heatthe mixture to reflux. After 5 h., add H₂O (100 mL) while the solutionis still hot, then cool to RT and acidify to pH=6 with 50% aqueousacetic acid. Wash with 1N NaOH, saturated NaHCO₃, and brine. Dry overNa₂SO₄, filter and concentrate. Purify the residue by columnchromatography over silica gel to provide the title compound (44%yield). MS(ES) 170.6 (M+1)⁺; R_(f)=0.55 (1:1 EtOAc/hexanes).

Preparation 280 (R,S)-2-amino-2-(2-chloro-phenyl)-acetamidehydrochloride

Stir a slurry of 2-chlorobenzaldehyde (43 ml, 1.0 eq) and sodiumbisulfite (39.5 g, excess) in H₂O (150 mL) and MeOH (150 mL) for 15 min,then add concentrated ammonium hydroxide (26 mL, 1.0 eq). Stir themixture for 30 min. at RT, then cool to 0° C. and add MeOH (75 mL) and asolution of sodium cyanide (18.7 g, 1.0 eq) in H₂O (75 mL) dropwise over15 min. Remove the ice bath and stir overnight. Evaporate off theorganics under reduced pressure, then extract the aqueous mixture withether. Wash the extracts with H₂O and brine, dry over Na₂SO₄, filter,and concentrate down to approximately 200 mL. Acidify the solution to pH4.5 with 2 N HCl. Cool the slurry in the refrigerator, filter theprecipitate, and dry under vacuum to give the title compound (3.3%yield). MS(FD) 186.63 (M+); IR (KBr) 2633.95, 1697.60, 1624.25, 1609.12,1588.63, 1502.62, 1478.18, 1424.98, 1346.50, 1310.12, 1192.24, 1149.58,1055.06, 1017.65, 760.25, 668.61, 659.94, 589.72, 478.19 cm⁻¹.

Preparation 281 (R/S)-3-amino-3-(2-chloro-phenyl)-propionic acid methylester

Add thionyl chloride (18.3 mL, 250 mmol) dropwise to a cooled (0° C.)flask containing MeOH (100 mL) under N₂. After 10 min., add thissolution dropwise to a stirred suspension of3-amino-3-(2-chloro-phenyl)-propionic acid (5.00 g, 25 mmol) in MeOH (50mL) and allow the mixture to warm to RT. After 48 h., concentrate themixture, add diethyl ether, and place in a sonicating bath for 10 min.Concentrate in vacuo to get the title compound as a white solid (6.29 g,quantitative yield). MS(ES) 214 (M+1)⁺. ¹H NMR (400 MHz, DMSO) δ3.05 (m,1H), 3.20 (m, 1H), 3.56 (s, 3H), 4.98 (t, 1H, J=7.3 Hz), 7.51 (m, 2H),7.54 (m, 1H), 7.81 (m, 1H), 8.84 (br s, 1H).

Preparation 282 (R/S)-3-amino-3-(2-chloro-phenyl)-propionic acid

Add 2-chlorobenzaldehyde (5.63 mL, 50 mmol), malonic acid (5.20 g, 50mmol), ammonium acetate (8.09 g, 105 mmol) and EtOH (20 mL) to amechanically stirred three-neck flask equipped with a condenser. Heatthe mixture to reflux and stir overnight. Cool to RT and filter theprecipitate, wash with EtOH and dry under reduced pressure to providethe title compound as a white solid (6.13 g, 61% yield). MS(ES) 200(M+1)⁺;

¹H NMR (400, MHz, D₂O/DCl) δ2.90 (m, 2H); 4.96 (t, 1H, J=7.8 Hz); 7.15(m, 2H); 7.26 (m, 2H).

Preparation 283 (R/S)-[1-(2-chloro-phenyl)-3-hydroxy-propyl]-carbamicacid tert-butyl ester

Add borane dimethylsulfide complex (12.7 mL of a 2.0M in THF, 25.5mmol,) dropwise to a 0° C. solution of3-tert-butoxycarbonylamino-3-(2-chloro-phenyl)-propionic acid methylester (2.50 g, 7.97 mmol) in THF (25 mL). Allow the reaction to warm toRT overnight, then quench with MeOH (30 mL), stir 30 min., andconcentrate. Dissolve the residue in 20% i-PrOH/CHCl₃, wash with 0.2NHCl, saturated aqueous NaHCO₃, and brine. Dry (MgSO₄) and concentrate invacuo. Purify the residue by chromatography on silica gel eluting with0-60% EtOAc/hexanes to provide the title compound as a white solid (2.15g, 94% yield). MS(ES) 286 (M+1)⁺; R_(f)=0.15 (25% EtOAc/hexanes).

Preparation 284(R/S)-3-tert-butoxycarbonylamino-3-(2-chloro-phenyl)-propionic acidmethyl ester

Add di-t-butyl-dicarbonate (6.32 mL, 27.5 mmol), DMAP (0.31 g, 2.5mmol), and pyridine (4.25 mL, 52.5 mmol) to a stirred suspension of3-amino-3-(2-chloro-phenyl)-propionic acid methyl ester (6.25 g, 25.0mmol) and stir at RT. After 16 h, concentrate the mixture and dissolvethe residue in 20% i-PrOH/CHCl₃. Wash with 0.1N HCl, saturated NaHCO₃solution, and brine. Dry (MgSO₄), filter, and concentrate. Purify bychromatography on silica gel, eluting with 0-15% EtOAc/hexanes, toprovide the title compound as a white solid (6.2 g, 94% yield). MS(ES)314(M+1)⁺; R_(f)=0.18 (15% EtOAc/hexanes).

Preparation 285 Acetic acid cis-2-(2-chloro-phenyl)-pyrrolidin-3-ylester

Combine 4-bromo-5-(2-chloro-phenyl)-3,4-dihydro-2H-pyrrole (3.2 g, 12.4mmol), silver acetate (2.48 g, 14.8 mmol), and potassium acetate (1.82g, 18.5 mmol) in glacial acetic acid (25 ml). Heat in an oil bath at100° C. for 1 h. Let cool to RT and remove most of the solvent. Dilutethe residue with EtOAc (75 ml) and slowly add saturated aqueous sodiumbicarbonate solution (50 ml). Wash the organic phase with brine (50 ml),dry over sodium sulfate, filter and concentrate. Purify the residue bychromatography on silica gel (15% EtOAc/hexanes) to give the desiredmaterial as a dark oil (1.34 g, 46%). Dissolve this material in glacialacetic acid and add sodium triacetoxyborohydride (3.58 g, 16.9 mmol).Stir at RT for 48 h, then remove most of solvent. Dilute the residuewith EtOAc (75 ml) and slowly add saturated aqueous sodium bicarbonatesolution (50 ml). Wash the organic phase with brine (50 ml), dry oversodium sulfate, filter and concentrate. Purify the residue bychromatography on silica gel (0.5% ammonium hydroxide/1%MeOH/dichloromethane) to give title compound as a dark oil (830 mg,61%). ¹H NMR (CDCl₃, 400 MHz) δ1.95-2.02 (m, 1H),2.07 (s,3H), 2.32-2.41(m, 1H), 3.03-3.1 (m, 1H), 3.32-3.38 (m, 1H), 4.57 (d, J=4.4 Hz, 1H),5.65-5.68 (m, 1H), 7.13-7.63 (m, 4H); R_(f)=0.2 (EtOAc, Ninhydrinstain).

Preparation 286 [4-(2-Chloro-phenyl)-2-hydroxy-4-oxo-butyl]-carbamicacid tert-butyl ester

Add titanium tetrachloride (1M solution in dichloromethane, 8.4 ml, 8.4mmol) to a solution of 1-(2-chloro-phenyl)-ethanone (1.24 g, 8.02 mmol)in dichloromethane (20 ml) at −78° C. Stir 10 min then adddiisopropylethylamine (965 mg, 7.46 ml) followed byN,N-bis(tert-butoxycarbonyl)glycinal in dichloromethane (20 ml).Continue to stir at −78° C. for 10 min, then warm to 0° C. for 30 min,and then warm to RT. After 2 h, quench the reaction with saturatedaqueous NH₄Cl (50 ml, extract with EtOAc (3×40 ml) and wash the combinedorganic layers with brine (50 ml). Dry over sodium sulfate, filter, andconcentrate. Purify the residue by chromatography on silica gel (10%EtOAc/hexanes and 25% EtOAc/hexanes) to give title compound as a viscousoil. ¹H NMR (CDCl₃, 400 MHz) δ1.45 (s, 9H), 3.10 (dd, J=18, 8.4 Hz, 1H),3.17-3.25 (m, 2H), 3.35-3.42 (m, 1H), 3.50 (br s, 1H), 4.30 (br s, 1H),5.01 (br s, 1H), 7.32-7.44 (m, 3H), 7.52 (d, J=6.8 Hz, 1H); R_(f)=0.2(40% EtOAc/hexanes).

Preparation 287[2-(tert-Butyl-dimethyl-silanyloxy)-4-(2-chloro-phenyl)-4-oxo-butyl]-carbamicacid tert-butyl ester

Combine [4-(2-chloro-phenyl)-2-hydroxy-4-oxo-butyl]-carbamic acidtert-butyl ester (570 mg, 1.82 mmol) and imidazole (248 mg, 3.64 mmol)in dichloromethane (5 ml), and chill to 0° C. Addtert-butyldimethylsilyl trifluoromenthanesulfonate (630 μl, 2.74 mmol)and stir for 12 h, allowing to slowly warm to RT. Dilute with EtOAc (40ml). Wash the organic phase with saturated aqueous NH₄Cl (30 ml) andsaturated aqueous NaHCO₃ (30 ml). Dry the organic phase over sodiumsulfate, filter, and concentrate. Purify the residue by chromatographyon silica gel (5% EtOAc/hexanes) to give the title compound as acolorless, viscous oil (530 mg, 68%). ¹H NMR (CDCl₃, 400 MHz) δ0.04 (s,3H), 0.11 (s, 3H), 0.85 (s, 9H), 1.43 (s, 9H), 3.07-3.36 (m, 4H), 4.44(br s, 1H), 4.76 (br s, 1H), 7.29-7.41 (m, 3H), 7.50 (d, J=8 Hz, 1H);R_(f)=0.46 (20% EtOAc/hexanes).

Preparation 288 4-(tert-Butyl-dimethyl-silanyloxy)-2-(2-chloro-phenyl)pyrrolidine

Dissolve[2-(tert-butyl-dimethyl-silanyloxy)-4-(2-chloro-phenyl)-4-oxo-butyl]-carbamicacid tert-butyl ester (530 mg, 1.24 mmol) and pyridine (0.3 ml, 3.72mmol) in acetonitrile (10 ml) and chill to 0° C. Add iodotrimethylsilane(0.3 ml, 2.11 mmol) and stir 15 min. Allow to warm to RT and stir anadditional 30 min. Dilute with EtOAc (40 ml) and wash with saturatedaqueous NH₄Cl (2×30 ml). Dry the organic phase over sodium sulfate,filter, and concentrate. Dissolve the residue in glacial acetic acid (10ml) and quickly add sodium triacetoxyborohydride (526 mg, 2.48 mmol).Stir at RT for 20 min., then remove most of solvent. Dissolve theresidue in EtOAc (40 ml) and wash with saturated aqueous sodiumbicarbonate solution (40 ml). Dry the organic phase over sodium sulfate,filter and concentrate. Purify the residue by chromatography onneutralized silica gel (10% EtOAc/hexanes) to give title compound as adark oil. ¹H NMR (CDCl₃, 400 MHz) δ0.00 (s, 3H), 0.03 (s, 3H), 0.83 (s,9H), 1.60 (ddd, J=12, 7.2, 4 Hz, 1H), 2.0 (br s, 1H), 2.51 (ddd, J=13.8,8, 6 Hz, 1H), 2.98-3.06 (m, 2H), 4.40-4.44 (m, 1H), 4.55 (t, J=8 Hz,1H), 7.11 (ddd, J=7.6, 7.6, 2 Hz, 1H), 7.19-7.23 (m, 1H), 7.28 (dd,J=8,1.6 Hz, 1H), 7.66 (dd, J=7.6, 2 Hz, 1H); R_(f)=0.5 (50%EtOAc/hexanes).

Preparation 289[1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl)-methanone

To a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (224 mg, 0.60 mmol) in CH₂Cl₂ (0.25 M), add oxalyl chloride (153mg, 1.2 mmol), followed by a catalytic amount of DMF (1 drop) and stirat RT. After 1 h, concentrate the mixture to dryness. To this residueadd a solution of 3-(2-chloro-phenyl)-piperidine (105 mg, 0.54 mmol) inpyridine (0.25 M), add a catalytic amount of DMAP (10 mg) and stir atRT. After 12 h, concentrate the solution. Dilute the residue with CH₂Cl₂(3 mL) and wash with 1N HCl (3×3 mL), and saturated solution of NaHCO₃(3 mL). Dry the organic layer, filter and concentrate to provide thetitle compound that was used without further purification (252 mg, 76%).R_(f)=0.34 2:1 Hex/EtOAc; MS(ES) 551.0 (M+1)⁺.

Preparation 290 (2-Chloro-benzyl)-(2,2,2-trifluoro-ethyl)-amine

Combine 2-iodo-1,1,1-trifluoroethane(1.15 g, 5.48 mmol) with2-chlorobenzyl amine (1.36 g, 9.6 mmol) and heat in a sealed vessel at100-170° C. After 16 h, cool to RT, quench with aqueous NaHCO₃, andextract with EtOAc. Dry over Na₂SO₄, filter, and concentrate. Purify bythe residue by chromatography on silica gel to provide the titlecompound (33% yield). MS(EI) 223.04 (M⁺); R_(f)=0.81 (CH₂Cl₂).

Preparation 291 2-(2-chloro-phenyl)-pyrrolidine-1-carboxylicacid-tert-butyl ester

Combine 2-(2-chloro-phenyl)-pyrrolidine (2.0 g, 11.0 mmol) withdi-t-butyldicarbonate (2.89 g, 13.2 mmol) in a mixture of THF (30 mL)and aqueous NaHCO₃ (30 mL) and stir at RT until the reaction iscomplete. Dilute the mixture with water and extract with EtOAc. Dry thecombined extracts over Na₂SO₄, filter, and concentrate. Purify theresidue by chromatography on silica gel to provide the title compound(92% yield). MS(ES) 282.3 (M+1)⁺; R_(f)=0.43 (CH₂Cl₂).

Preparation 292 2-(2-chloro-phenyl)-2-methyl-pyrrolidine-1-carboxylicacid-tert-butyl ester

Combine 2-(2-chloro-phenyl)-pyrrolidine-1-carboxylic acid-tert-butylester (2.0 g, 7.12 mmol) and TMEDA (1.16 mL, 14.2 mmol) in THF (100 mL)and cool the mixture to −78° C. Slowly add a solution of s-butyl lithium(1.3 M in cyclohexane, 10.95 mL) and stir for 1-2 h with cooling. Addiodomethane (1.14 mL, 14.2 mmol) in one portion and allow the mixture tostir for 1-2 h while warming to −20° C. Quench the reaction with waterand extract with EtOAc. Dry the combined extracts over Na₂SO₄, filter,and concentrate. Purify the residue by chromatography on silica gel toprovide the title compound (37% yield). MS(ES) 296.4 (M+1)⁺; R_(f)=0.24(CH₂Cl₂).

Preparation 293 2-(2-Chloro-phenyl)-2-methyl-pyrrolidine hydrochloride

Dissolve 2-(2-chloro-phenyl)-2-methyl-pyrrolidine-1-carboxylicacid-tert-butyl ester (0.76 g, 2.58 mmol) in acetic acid saturated withHCl (5 mL) and stir at RT. After 4 h, concentrate the mixture underreduced pressure, and then concentrate the residue twice from Et₂O togive the title compound (94% yield) that was used without furtherpurification. MS(ES) 196.0 (M+1)⁺.

Preparation 2941-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-isopropyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (0.25 g, 0.67 mmol) in CH₂Cl₂ (5 mL). Add DMF (1 drop, cat.) andoxalyl chloride (0.18 mL, 2.1 mmol) and stir at RT. After 1 h,concentrate the mixture under reduced pressure, redissolve in Et₂O andconcentrate again. Add pyridine (5 mL),(2-chloro-phenyl)-isopropyl-amine (0.113 g, 0.67 mmol), and DMAP (10 mg)and heat to 50° C. until the reaction is complete. Cool to RT, quenchthe reaction with aqueous NaHCO₃, and extract with EtOAc. Dry thecombined extracts over Na₂SO₄, filter, and concentrate. Purify theresidue by chromatography on silica gel to provide the title compound.R_(f)=0.60 (6.25% MeOH/CH₂Cl₂).

Preparation 2951-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid methyl ester

Add 3,5-bis triflouromethyl benzyl amine (5.66 g, 23.3 mmol) andtriethylamine (2.7 mL, 19.4 mmol) to a solution(E/Z-3-bromo-2-methyleneamino-3-phenyl-acrylic acid methyl ester (5.20g, 19.4 mmol, J. Org. Chem. 1994, 59, 7635) in DMF (60 mL). Stir thereaction mixture at RT for 16 h, then pour into saturated aqueous NaHCO₃and extract with CH₂Cl₂ (once), and EtOAc (three times). Dry thecombined organic layers over magnesium sulfate, filter, and concentrate.Remove excess DMF by azeoptropic distillation at reduced pressure withxylenes. Purify the residue by chromatography on silica gel using ahexanes/EtOAc gradient to yield the title compound (3.0 g, 36%) as abrown-orange solid. ¹H NMR (300 MHz, CDCl₃) 7.79 (s, 1H), 7.75 (s 1H),7.35-7.5 (m, 3H), 7.25-7.49 (m, 4H), 5.15 (s, 2H), 3.77 (s, 3H); MS(ES)429.1 (M+1)⁺.

Preparation 296 1-Phenethyl-5-phenyl-1H-imidazole-4-carboxylic acidmethyl ester

Using a method similar to the above Preparation, with the appropriatestarting materials, the title compound may be prepared and isolated. ¹HNMR 7.55-7.45 (m, 4H), 7.20-7.35 (M, 5H), 6.85-6.75 (m, 2 H), 4.05 (t, 2H), 3.75 (s, 3H), 2.85 (t, 2H); MS(ES) 307.2 (M+1)⁺.

Preparation 2971-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-4-fluoro-phenyl)-amide

Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl1H-[1,2,3]triazole-4-carboxylic acid (398 mg, 0.96 mmol) in1,2-dichloromethane (2 mL) and DMF (2 drops) and add oxalyl chloride(0.083 mL, 0.96 mmol). After 1 h, concentrate the mixture under reducedpressure and dissolve the residue in pyridine (3 mL). Add2-chloro-4-fluoroaniline (0.12 mL, 0.96 mmol) and DMAP (5 mg) and heatthe mixture for 1 h at 100° C. Then cool the mixture to RT andconcentrate under reduced pressure. Dissolve the residue in 20%iPrOH/CHCl₃ and wash with sat. aqueous NaHCO₃ and brine. Dry the organiclayer over Na₂SO₄, filter and concentrate. Purify the residue by radialchromatography (MeOH/CHCl₃ gradient) to provide 93 mg (36%) of the titlecompound as a white foam. MS(ES) 543.0 (M+1)⁺; R_(f)=0.85 (2%MeOH/CHCl₃).

Preparation 2981-(3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add 0.5M solution of sodium methoxide in MeOH (4.0 mL, 2.0 mmol) to1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole4-carboxylicacid (2-chloro-benzyl)-methyl-amide (0.2 g, 0.4 mmol) and reflux for 18h. Acidify the reaction mixture with IN HCl to pH 4, collect precipitateby filtration, and dry to give the product as white powder (0.12 g,60%). MS(ES) 493.1 (M+1)⁺. ¹H NMR (400 MHz, DMSO, 1:1 mixture ofrotamers): δ8.13 (s, 0.5H), 8.12 (s, 0.5H), 8.02 (s, 1H), 7.94 (s, 1H),7.45 (m, 1H), 7.34 (m, 1H), 7.27 (m, 2H), 5.62 (s, 1H), 5.58 (s, 1H),5.25 (s, 1H), 4.75 (s, 1H), 3.40 (s, 1.5H), 2.95 (s, 1.5H).

EXAMPLE 1(R)-3-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-4-phenyl-oxazolidin-2-one.

Add triethylamine (0.156 mL, 1.12 mmol) to a slurry of1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (150 mg, 0.36 mmol) and (R)-(−)-4-phenyl-2-oxazolidinone (46 mg,0.28 mmol) in toluene (5 mL). Heat the mixture to 90° C., then addpivaloyl chloride (0.044 mL, 0.36 mmol). Reflux overnight, then cool toRT and concentrate under reduced pressure. Dissolve the residue in 20%iPrOH/CHCl₃ and wash with saturated aqueous NaHCO₃, and brine, dry overNa₂SO₄, filter, and concentrate. Purify the residue by radialchromatography (EtOAc/hexanes gradient) to afford the title compound (35mg, 23%) as a white foam. MS(ES) 561.2 (M+1)⁺; HPLC [40% iPrOH 60%heptane on a chiralpack AD (0.46×25 cm) 1.5 mL/min flow, 0.020 mL Inj.Vol.; 222 nM] R_(f)=10.3 min; 92.9%.

Using the method of Example 1, the following compounds may be preparedand isolated.

Ex. # R^(A) R^(B) Data 2 (S)- hydrogen MS(ES) 561.07 (M + 1)⁺; HPLC (40%phenyl iPrOH 60% heptane on a chiralpack AD (0.46 × 25 cm) 1.5 mL/minflow, 0.020 mL Inj. Vol.; 222 nM) R_(f) = 9.44 min; 94.2%. 3 (R)-hydrogen MS(ES) 575.0 (M + 1)⁺; HPLC (40% iPrOH benzyl 60% heptane on achiralpack AD (0.46 × 25 cm) 1.5 mL/min flow, 0.020 mL Inj. Vol.; 222nM) R_(f) = 12.3 min; 95.3%. 4 (S)- hydrogen MS(ES) 575.0 (M + 1)⁺; HPLC(40% iPrOH benzyl 60% heptane on a chiralpack AD (0.46 × 25 cm) 1.5mL/min flow, 0.020 mL Inj. Vol.; 222 nM) R_(f) = 12.01 min; 92.6%. 5(R)- (S)- MS(ES) 637.1 (M + 1)⁺. HPLC (40% iPrOH phenyl phenyl 60%heptane on a chiralpack AD (0.46 × 25 cm) 1.5 mL/min flow, 0.020 mL Inj.Vol.; 222 nM) R_(f) = 23.78 min; 99.3%. 6 (S)- (R)- MS(ES) 637.2 (M +1)⁺. HPLC (40% iPrOH phenyl phenyl 60% heptane on a chiralpack AD (0.46× 25 cm) 1.5 mL/min flow, 0.020 mL Inj. Vol.; 222 nM) R_(f) = 22.86 min;96.1%. 7 (S)- dimethyl MS(ES) 589.2 (M + 1)⁺; TLC R_(f) = 0.75 phenyl(50% EtOAc/hexanes).

EXAMPLE 8 2-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-1-phenyl-pyrazolidin-3-one.

Using a method similar to Example 1, with the exception of using1-phenyl-3-pyrazolidinone (46 mg, 0.28 mmol, Aldrich), affords the titlecompound (11.0 mg, 7.5%) as a white foam. MS(ES) 560.0 (M+1)⁺; TLCR_(f)=0.37 (50% EtOAc/hexanes).

EXAMPLE 91-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-]H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide.

Add oxalyl chloride (0.064 mL, 0.72 mmol) to a solution of1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (150 mg, 0.36 mmol) and DMF (1 drop) in CH₂Cl₂ (2 mL). Stir thesolution for 2.5 h at RT, then concentrate to dryness. Dissolve theresidue in 1,2-dichloroethane (DCE) and concentrate to dryness. Dissolvethe residue in pyridine (2 mL) and transfer to a sealed tube. Add2-chloro-N-methylaniline (200 mg, 1.44 mmol) and DMAP (5 mg, cat.) andheat in the sealed tube at 80° C. for 1h. Cool to RT and concentrate todryness. Dissolve in 20% iPrOH/CHCl₃. Wash with saturated NaHCO₃ andbrine, dry over Na₂SO₄, filter and concentrate to dryness. Purify byradial chromatography using an EtOAc/hexanes gradient to afford thetitle compound (75.4 mg, 39%) as a clear foam/oil. MS(ES) 539.2 (M+1)⁺;HPLC (5-95% 0.1% TFA/water in 3.8 min on YMC ODS (0.46×50mm) .05 mL; 3.0mL; 25° C.) R_(f)=3.34 min; 99.2%.

Using an analogous procedure to that described above, with theappropriate starting materials, the following compounds may be prepared.

Ex. # R² R³ R⁵ Data 10. hydroxyl benzyl phenyl MS(ES) 521.2 (M + 1)⁺; ¹HNMR (CDCl₃) δ 7.70 (m, 1H), 7.10-7.60 (m, 14H), 5.50-5.60 (m, 3H). 112,4-dichloro- methyl phenyl MS(ES) 573.0 (M + 1)⁺; phenyl R_(f) = 0.70(5% MeOH/CHCl₃). 12 2-chloro-4- methyl methyl MS(ES) 491.0 (M + 1)⁺;methyl-phenyl R_(f) = 0.33 (5% MeOH/CHCl₃). 13 2-chloro-4- methyl methylMS(ES) 495.0 (M + 1)⁺; fluoro-phenyl R_(f) = 0.60 (5% MeOH/CHCl₃). 142-chloro- methyl methyl MS(ES) 477.3 (M + 1)⁺; phenyl R_(f) = 0.31 (5%MeOH/CHCl₃).

Using a method analogous to Example 9 and the appropriate startingmaterials, the following compounds may be prepared.

Ex. # R⁵ R⁸ R⁹ Data 15 phenyl 2-chloro-phenyl oxo MS(ES) 594.1 (M + 1)⁺;R_(f) = 0.6 (50% EtOAc/hexanes). 16 methyl 2-chloro-phenyl hydrogenMS(ES) 518.0 (M + 1)⁺; R_(f) = 0.29 (5% MeOH/CHCl₃).

EXAMPLE 171-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-3,(4S)-dimethyl-(5R)-(+)-phenyl-imidazolidin-2-one.

Using a method similar to Example 1, with the exception of using(4S,5R)-(+)-1,5-dimethyl-4-phenyl-2-imidazolidinone (52 mg, 0.28 mmol),affords the title compound (11.7 mg, 7.1%) as a white foam. MS(ES) 588.2(M+1)⁺; R_(f)=0.54 (80% EtOAc/hexanes).

EXAMPLE 181-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-3,(4R)-dimethyl-(5S)-(−)-phenyl-imidazolidin-2-one

Add oxalyl chloride (0.064 mL, 0.72 mmol) to a solution of1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (150 mg, 0.36 mmol) in CH₂Cl₂ (2 mL) and DMF (1 drop). Stir thesolution for 2 hours at RT, then concentrate to dryness. Dissolve in1,2-dichloroethane and concentrate to dryness. Dissolve in THF (2 mL)and set aside. This is solution A. Add n-butyllithium (0.15 mL, 0.36mmol) to a solution of(4R,5S)-(−)-1,5-dimethyl-4-phenyl-2-imidazolidinone (62 mg, 0.32 mmol,Aldrich) in THF (2 mL) at −78° C. Stir for 10 min at −78° C., then addSolution A at −78° C. Stir the mixture for 15 min. at −78° C., thenremove cold bath and warm to RT over 1 h. Concentrate to dryness anddissolve in 20% iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃ andbrine, dry over Na₂SO₄, filter, and concentrate. Purify by radialchromatography using an EtOAc/hexanes gradient to afford the titlecompound (23 mg, 12.5%) as a white foam. MS(ES) 588.3 (M+1)⁺; R_(f)=0.50(80% EtOAc/hexanes).

EXAMPLE 191-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-4-fluoro-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-4-fluoro-phenyl)-amide (80 mg, 0.15 mmol) in THF (2 mL).Add potassium hexamethyl disilylamide (0.33 mL, 0.17 mmol, 0.5 M intoluene) and methyl iodide (0.011 mL, 0.17 mmol). Stir overnight at RT,then partition between EtOAc and saturated aqueous NaHCO₃. Wash withsaturated aqueous NaHCO₃, and brine, dry over sodium sulfate, filter,and concentrate to dryness. Purify the residue by radial chromatographyusing an EtOAc/hexanes gradient to afford 30 mg (36%) of the titlecompound as a white foam. MS(ES) 557.0 (M+1)⁺; R_(f)=0.48 (1:1EtOAc/hexanes).

EXAMPLE 201-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-4-methyl-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (100 mg, 0.24 mmol) in CH₂Cl₂ (3 mL) and DMF (1 drop) and addoxalyl chloride (0.042 mL, 0.48 mmol). Stir 1 h at RT, then concentrate.Slurry the residue in 1,2-dichloroethane and concentrate to drynesstwice. Dissolve the residue in pyridine (2 mL), add DMAP (5 mg,catalytic) and (2-chloro-4-methyl-phenyl)-methyl-amine (0.74 mg, 0.48mmol) and heat for 1 h at 100° C. in a sealed tube, then cool to RT andconcentrate to dryness. Dissolve in 20% iPrOH/CHCl₃. Wash with saturatedaqueous NaHCO₃ and brine, dry over Na₂SO₄, filter, and concentrate.Purify the residue via radial chromatography using a MeOH/CHCl₃ gradientto afford 67 mg (48%) of the title compound as a yellow foam/oil. MS(ES)553.0 (M+1)⁺; R_(f)=0.42 (5% MeOH/CHCl₃).

EXAMPLE 211-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-pyridin-3-ylmethyl)-methyl-amide

Combine (2-chloro-pyridin-3-ylmethyl)-methyl-amine (0.050 g, 0.32 mmol)with1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (0.10 g, 0.24 mmol), EDCI (0.046 0.24 mmol),1-hydroxy-7-azabenzotriazole (0.033 g, 0.24 mmol), andN,N-diisopropylethylamine (0.10 mL, 0.56 mmol), in DMF (6 mL) and stirthe mixture at RT. After 72 h, concentrate the mixture in vacuo andpartition the residue between water and CH₂Cl₂. Separate the layers anddry the CH₂Cl₂ extracts over Na₂SO₄. Filter and concentrate, then purifythe residue over silica gel using a MeOH/CH₂Cl₂ gradient to provide thetitle compound (0.123 g, 92%) as a white solid. MS(ES) 554.1 (M+1)⁺;Anal. Calc'd for C₂₅H₁₈ClF₆N₅O: C, 54.21; H, 3.28; N, 12.64. Found: C,53.83; H, 3.31; N, 12.33.

Using a method analogous to Example 21, with the appropriate startingmaterials, the following compounds may be prepared.

Ex. # R² Data 22 3-chloro-pyridin- MS(ES) 554.1 (M + 1)⁺; Anal. Calc'dfor 4-yl-methyl C₂₅H₁₈ClF₆N₅O: C, 54.21; H, 3.28; N, 12.64. Found: C,53.39; H, 3.49; N, 11.99. 23 4-chloro-pyridin- MS(ES) 554.1 (M + 1)⁺.R_(f) = 0.34 (10:1 3-yl-methyl CHCl₃/MeOH).

Using a method analogous to Example 21, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R^(A) Data 24 pyridin-2-yl MS(ES) 546.1 (M + 1)⁺; Anal. Calc'd forC₂₇H₂₁F₆N₅O: C, 59.45; H, 3.88; N, 12.84. Found: C, 59.29; H, 4.06; N,13.15. 25 pyridin-4-yl MS(ES) 546.1 (M + 1)⁺; Anal. Calc'd forC₂₇H₂₁F₆N₅O: C, 59.45; H, 3.88; N, 12.84. Found: C, 59.29; H, 3.98; N,13.12. 26 benzyl MS(ES) 559.19 (M + 1)⁺; R_(f) = 0.85 (10:1 CHCl₃/MeOH).27 phenethyl MS(ES) 573.2 (M + 1)⁺; R_(f) = 0.76 (10:1 CHCl₃/MeOH). 28cyclohexyl MS(ES) 551.2 (M + 1)⁺; R_(f) = 0.62 (10:1 CHCl₃/MeOH). 29isobutyl MS(ES) 525.2 (M + l)⁺; R_(f) = 0.53 (10:1 CHCl₃/MeOH). 30pyridin-3-yl- MS(ES) 560.1 (M + 1)⁺; R_(f) = 0.28 methyl (10:1CHCl₃/MeOH).

Using the method similar to Example 21, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Ex. #Product Data 31 1-Phenethyl-5-phenyl-1H- MS(ES) 559.2(M+1)⁺;[1,2,3]triazole-4-carboxylic R_(f)=0.82(10:1 acid(3,5-bis-trifluoromethyl-benzyl)- CHCl₃/MeOH) cyclopropyl-amide 321-Phenethyl-5-phenyl-1H- MS(ES) 561.2(M+1)+;[1,2,3]triazole-4-carboxylic R_(f)=0.79(10:1 acid(3,5-bis-trifluoromethyl-benzyl)- CHCl₃/MeOH) isopropyl-amide

EXAMPLE 331-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-isopropyl-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (0.15 g, 0.36 mmol) and DMF (1 drop) in CH₂Cl₂ (5 mL) and slowlyadd oxalyl chloride (0.10 mL, 1.14 mmol) via syringe and stir until gasevolution ceases. Concentrate the mixture in vacuo and concentrate theresidue once from diethyl ether. Dissolve this crude acid chloride inpyridine (5 mL) and add (2-chlorophenyl)-isopropyl-1 mg, 0.36 mmol) andDMAP (3 mg). Heat the mixture at 100° C. for 1 h, then cool to RT andconcentrate. Partition the residue between water and EtOAc and dry thecombined extracts over Na₂SO₄. Concentrate the extracts and purify theresidue by chromatography over silica gel using a CH₂Cl₂/MeOH gradientto provide the title compound (113 mg, 55%) as a thick oil whichsolidifies. MS(ES) 567.1 (M+1)⁺; R_(f)=0.61 (6.7% MeOH/CH₂Cl₂).

EXAMPLE 341-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-(2-dimethylamino-ethyl)-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (160 mg, 0.37 mmol) in dry CH₂Cl₂ (0.2M) addN′-(2-chlorobenzyl)-N,N-dimethyl-ethane-1,2-diamine (78 mg, 0.37 mmol),followed by triethylamine (0.26 mL, 1.85 mmol). After 24 h, dilute withCH₂Cl₂ (2 mL) and wash with 1N NaOH (2×3 mL), dry, filter, andconcentrate. Purify the residue by chromatography (50:1 to 20:1CHCl₃/MeOH gradient) to provide the title compound. MS(ES) 610.1 (M+1)⁺;R_(f)=0.44 (10:1 CHCl₃/MeOH).

By a method analogous to Example 34, the following compounds may beprepared and isolated.

Ex. # —NR⁶R⁷ Data 35 pyrrolidin-1-yl MS/ES: 636.2 (M + 1); R_(f) = 0.42(10:1 CHCl₃/MeOH). 36 morpholino MS/ES: 652.1 (M + 1); R_(f) = 0.15(10:1 CHCl₃/MeOH).

EXAMPLE 375-Phenyl-1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid benzyl-methyl-amide

Add 3-(trifluoromethyl)benzyl azide (1.2 eq) to a solution of3-phenyl-propynoic acid benzyl-methyl-amide (1 eq) in toluene (0.3 M).Heat the resulting solution at 120° C. in a sealed (screw-cap) test tubeusing a block heater that is placed on an orbital shaker for agitation.After 48 h, cool to RT and apply the reaction mixture directly to thetop of a pre-packed silica gel column. Elution with a hexanes/EtOAcgradient provides two regioisomeric triazoles. The desired product isthe slower eluting (lower R_(f)) spot. R_(f)=0.18 (2:1 hexanes/EtOAc);MS(ES): 451.2 (M+1)⁺.

Using a method analogous to Example 37, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # D¹ R^(a) R² Data 38 methylene 2- benzyl R_(f) = 0.23 (2:1hexanes/EtOAc); trifluoromethyl MS(ES) 451.2 (M + 1)⁺. 39 methylene3-fluoro benzyl R_(f) = 0.15 (2:1 hexanes/EtOAc); MS(ES) 401.2 (M + 1)⁺.40 ethylene hydrogen benzyl R_(f) = 0.13 (2:1 hexanes/EtOAc); MS(ES)397.2 (M + 1)⁺. 41 ethylene 3-methyl benzyl R_(f) = 0.15 (2:1hexanes/EtOAc); MS(ES) 411.2 (M + 1)⁺. 42 ethylene 3-trifluoro- benzylR_(f) = 0.10 (2:1 hexanes/EtOAc); methyl MS(ES) 465.2 (M + 1)⁺. 43propane-2,3-diyl hydrogen benzyl R_(f) = 0.20 (2:1 hexanes/EtOAc);MS(ES) 411.2 (M + 1)⁺. 44 methylene 3,5-bis- benzyl R_(f) = 0.15 (2:1hexanes/EtOAc); trifluoromethyl MS(ES) 519.2 (M + 1)⁺. 45 methylene3,5-dichloro benzyl R_(f) = 0.18 (2:1 hexanes/EtOAc); MS(ES) 451.1 (M +1)⁺. 46 methylene 3,5-dimethyl benzyl R_(f) = 0.23 (2:1 hexanes/EtOAc);MS(ES) 411.1 (M + 1)⁺. 47 ethylene 4-methoxy 3,5-dimethyl- R_(f) = 0.13(2:1 hexanes/EtOAc); benzyl MS(ES) 455.3 (M + 1)⁺. 48 ethylene 4-methoxy3,5-dichloro- R_(f) = 0.13 (2:1 hexanes/EtOAc); benzyl MS(ES) 495.2 (M +1)⁺. 49 ethylene 4-methoxy 3-fluoro-5- R_(f) = 0.15 (2:1 hexanes/EtOAc);trifluoromethyl-benzyl MS(ES) 513.2 (M + 1)⁺. 50 ethylene 3,5-bis-benzyl R_(f) = 0.15 (2:1 hexanes/EtOAc); trifluoromethyl MS(ES) 533.2(M + 1)⁺. 51 methylene 3-chloro benzyl R_(f) = 0.15 (2:1 hexanes/EtOAc);MS(ES) 417.1 (M + 1)⁺. 52 methylene 3,5-dibromo benzyl R_(f) = 0.20 (2:1hexanes/EtOAc); MS(ES) 541.0 (M + 1)⁺. 53 methylene 3,5-bis- phenethylR_(f) = 0.20 (2:1 hexanes/EtOAc); trifluoromethyl MS(ES) 533.2 (M + 1)⁺.54 methylene 3,5-dichloro phenethyl R_(f) = 0.18 (2:1 hexanes/EtOAc);MS(ES) 465.1 (M + 1)⁺. 55 methylene hydrogen 2-chloro-benzyl R_(f) =0.23 (2:1 hexanes/EtOAc); MS(ES) 417.1 (M + 1)⁺. 56 methylene3,5-dimethyl 2-chloro-benzyl R_(f) = 0.30 (2:1 hexanes/EtOAc); MS(ES)445.2 (M + 1)⁺. 57 methylene 3,5-dibromo 2-chloro-benzyl R_(f) = 0.26(2:1 hexanes/EtOAc); MS(ES) 575.0 (M + 1)⁺. 58 methylene 3,5-dichloro2-chloro-benzyl R_(f) = 0.26 (2:1 hexanes/EtOAc); MS(ES) 485.1 (M + 1)⁺.59 methylene 2-chloro 2-chloro-benzyl R_(f) = 0.26 (2:1 hexanes/EtOAc);MS(ES) 451.1 (M + 1)⁺. 60 methylene 3-chloro 2-chloro-benzyl R_(f) =0.20 (2:1 hexanes/EtOAc); MS(ES) 451.1 (M + 1)⁺. 61 methylene 4-methoxy2-chloro-benzyl R_(f) = 0.17 (2:1 hexanes/EtOAc); MS(ES) 447.1 (M + 1)⁺.62 methylene 3-trifluoro- 2-chloro-benzyl R_(f) = 0.26 (2:1hexanes/EtOAc); methyl MS(ES) 485.1 (M + 1)⁺. 63 methylene 2-methyl2-chloro-benzyl R_(f) = 0.26 (2:1 hexanes/EtOAc); MS(ES) 431.1 (M + 1)⁺.64 methylene 3-methyl 2-chloro-benzyl R_(f) = 0.29 (2:1 hexanes/EtOAc);MS(ES) 431.1 (M + 1)⁺. 65 methylene 4-methyl 2-chloro-benzyl R_(f) =0.29 (2:1 hexanes/EtOAc); MS(ES) 431.1 (M + 1)⁺. 66 methylene hydrogen3,5-bis-trifluoro- R_(f) = 0.32 (2:1 hexanes/EtOAc); methyl-benzylMS(ES) 519.1 (M + 1)⁺. 67 methylene 2-methyl 3,5-bis-trifluoro- R_(f) =0.34 (2:1 hexanes/EtOAc); methyl-benzyl MS(ES) 533.1 (M + 1)⁺. 68methylene 3-methyl 3,5-bis-trifluoro- R_(f) = 0.34 (2:1 hexanes/EtOAc);methyl-benzyl MS(ES) 533.1 (M + 1)⁺. 69 methylene 4-methyl3,5-bis-trifluoro- R_(f) = 0.29 (2:1 hexanes/EtOAc); methyl-benzylMS(ES) 533.1 (M + 1)⁺. 70 methylene 2-chloro 3,5-bis-trifluoro- R_(f) =0.29 (2:1 hexanes/EtOAc); methyl-benzyl MS(ES) 553.0 (M + 1)⁺. 71methylene 3-chloro 3,5-bis-trifluoro- R_(f) = 0.26 (2:1 hexanes/EtOAc);methyl-benzyl MS(ES) 553.1 (M + 1)⁺. 72 ethylene 2-methoxy3,5-bis-trifluoro- R_(f) = 0.23 (2:1 hexanes/EtOAc); methyl-benzylMS(ES) 563.2 (M + 1)⁺. 73 ethylene hydrogen 3,5-bis-trifluoro- R_(f) =0.20 (2:1 hexanes/EtOAc); methyl-benzyl MS(ES) 533.2 (M + 1)⁺. 74ethane-1,1-diyl 3- benzyl R_(f) = 0.23 (2:1 hexanes/EtOAc);trifluoromethyl MS(ES) 465.2 (M + 1)⁺. 75 ethane-1,1-diyl 3-2-chloro-benzyl R_(f) = 0.29 (2:1 hexanes/EtOAc); trifluoromethyl MS(ES)499.2 (M + 1)⁺. 76 methylene 4-methyl benzyl R_(f) = 0.20 (2:1hexanes/EtOAc); MS(ES) 397.3 (M + 1)⁺. 77 methylene 2-methoxy benzylR_(f) = 0.14 (2:1 hexanes/EtOAc); MS(ES) 413.2 (M + 1)⁺. 78 methylene3-methoxy benzyl R_(f) = 0.14 (2:1 hexanes/EtOAc); MS(ES) 413.2 (M +1)⁺. 79 methylene 2-bromo benzyl R_(f) = 0.20 (2:1 hexanes/EtOAc);MS(ES) 461.1 (M⁺), 463.1 (M + 2)⁺. 80 ethylene 3- 3,5-dimethyl- MS(ES)493.3 (M + 1)⁺; R_(f) = 0.31 trifluoromethyl benzyl (2:1 hexanes/EtOAc).81 ethylene 3- 3,5-dichloro- MS(ES): 533.1 (M + 1)⁺; R_(f) =trifluoromethyl benzyl 0.16 (2:1 hexanes/EtOAc). 82 ethylene 3-3-fluoro-5-trifluoro- MS(ES) 551.2 (M + 1)⁺; R_(f) = 0.13trifluoromethyl methyl-benzyl (2:1 hexanes/EtOAc). 83 ethylene 3-5-chloro-2- MS(ES) 529.2 (M + 1)⁺; R_(f) = 0.09 trifluoromethylmethoxy-benzyl (2:1 hexanes/EtOAc). 84 ethane-1,1-diyl 4-fluoro benzylMS(ES) 415.2 (M + 1)⁺; R_(f) = 0.26 (2:1 hexanes/EtOAc). 85 ethylene 3-5-fluoro-2- MS(ES) 513.2 (M + 1)⁺; R_(f) = 0.12 trifluoromethylmethoxy-benzyl (2:1 hexanes/EtOAc). 86 ethylene 3-2-methoxy-5-trifluoro- MS(ES) 579.2 (M + 1)⁺; R_(f) = 0.10trifluoromethyl methoxy-benzyl 87 ethylene 3- 2-chloro-benzyl MS(ES)499.1 (M + 1)⁺; R_(f) = 0.14 trifluoromethyl (2:1 hexanes/EtOAc). 88ethane-1,1-diyl 3-methyl benzyl MS(ES) 411.2 (M + 1)⁺; R_(f) = 0.30 (2:1hexanes/EtOAc). 89 ethylene 4-fluoro benzyl MS(ES) 415.2 (M + 1)⁺; R_(f)= 0.25 (2:1 hexanes/EtOAc). 90 propane- hydrogen benzyl MS(ES) 411.2(M + 1 )⁺; R_(f) = 0.15 1,3-diyl (2:1 hexanes/EtOAc). 91 propane-4-methoxy benzyl MS(ES) 441.3 (M + 1)⁺; R_(f) = 0.40 1,3-diyl (2:1hexanes/EtOAc). 92 ethylene 4-ethoxy benzyl MS(ES) 441.2 (M + 1)⁺; R_(f)= 0.14 (2:1 hexanes/EtOAc). 93 methylene 3,5-bis- 3-fluoro-5- MS(ES)605.2 (M + 1)⁺; R_(f) = 0.28 trifluoromethyl trifluoromethyl-benzyl (2:1hexanes/EtOAc). 94 methylene 3,5-bis- 5-fluoro-2- MS(ES) 567.2 (M + 1)⁺;R_(f) = 0.21 trifluoromethyl methoxy-benzyl (2:1 hexanes/EtOAc): 95methylene 3,5-bis- 3,5-dimethyl- MS(ES) 547.2 (M + 1)⁺; R_(f) = 0.30trifluoromethyl benzyl (2:1 hexanes/EtOAc). 96 methylene 3,5-bis-5-chloro-2- MS(ES) 583.1 (M + 1)⁺; R_(f) = 0.15 trifluoromethylmethoxy-benzyl (2:1 hexanes/EtOAc). 97 methylene 3,5-bis-2-methoxy-5-trifluoro- MS(ES) 633.2 (M + 1)⁺; R_(f) = 0.30trifluoromethyl methoxy-benzyl (2:1 hexanes/EtOAc).

By a method analogous to Example 37, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # D¹ R^(a) Data 98 methylene 3,5-bis- R_(f) = 0.38; MS(ES) 595.2(M + 1) trifluoromethyl 99 ethylene 3-trifluoromethyl R_(f) = 0.36;MS(ES) 541.3 (M + 1);

EXAMPLE 1001-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Suspend1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (100 mg, 1 eq) and HOBt (64 mg, 2 eq) in dry CH₂Cl₂ (2.4 mL, 0.1 Msolution). Add N-methyl-N-(2-chlorobenzyl) amine (66 mg, 1.5 eq) andtriethylamine (0.17 mL, 5 eq) followed by EDCI (92 mg, 2 eq). Stir at RTovernight, then dilute with CH₂Cl₂ (5 mL) and wash with 1N HCl solution,saturated NaHCO₃ solution, and brine. Dry over MgSO₄, filter, andconcentrate. Purify the residue by flash chromatography on silica gelusing a 4:1 to 1:1 hexanes/EtOAc gradient to provide the title compound(118 mg, 89%) as a pale yellow oil that crystallizes upon standing.R_(f)=0.35 (2:1 hexanes/EtOAc); MS(ES) 553.2 (M+1)⁺.

By a method analogous to Example 100, the following compounds may beprepared and isolated.

Ex. # R² R³ Data 101 2-fluoro-benzyl methyl R_(f) = 0.25 (2:1hexanes/EtOAc); MS(ES) 537.2 (M + 1)⁺. 102 4-fluoro-benzyl methyl R_(f)= 0.15 (2:1 hexanes/EtOAc); MS(ES) 537.2 (M + l)⁺. 103 3-methyl-benzylmethyl R_(f) = 0.23 (2:1 hexanes/EtOAc); MS(ES) 533.2 (M + 1)⁺. 1042-methoxy-benzyl methyl R_(f) = 0.15 (2:1 hexanes/EtOAc); MS(ES) 549.2(M + 1)⁺. 105 3-methoxy-benzyl methyl R_(f) = 0.18 (2:1 hexanes/EtOAc);MS(ES) 549.2 (M + 1)⁺. 106 4-methoxy-benzyl methyl R_(f) = 0.18 (2:1hexanes/EtOAc); MS(ES) 549.2 (M + 1)⁺. 107 4-chloro-benzyl methyl R_(f)= 0.23 (2:1 hexanes/EtOAc); MS(ES) 553.2 (M + 1)⁺. 108 3-chloro-benzylmethyl R_(f) = 0.20 (2:1 hexanes/EtOAc); MS(ES) 553.2 (M + 1)⁺. 1094-trifluoromethyl- methyl R_(f) = 0.20 (2:1 hexanes/EtOAc); benzylMS(ES) 587.2 (M + 1). 110 4-pyrrolidin-1-yl- methyl R_(f) = 0.18 (2:1hexanes/EtOAc); benzyl MS(ES) 588.1 (M + 1)⁺ 111 4-dimethylamino- methylR_(f) = 0.15 (2:1 hexanes/EtOAc); benzyl MS(ES) 562.1 (M + 1)⁺. 1122-methyl-benzyl methyl R_(f) = 0.25 (2:1 hexanes/EtOAc); MS(ES) 533.2(M + 1)⁺. 113 4-methyl-benzyl methyl R_(f) = 0.25 (2:1 hexanes/EtOAc);MS(ES) 533.2 (M + 1)⁺. 114 3-fluoro-benzyl methyl R_(f) = 0.33 (2:1hexanes/EtOAc); MS(ES) 537.2 (M + 1)⁺. 115 2-trifluoromethyl- methylR_(f) = 0.35 (2:1 hexanes/EtOAc); benzyl MS(ES) 587.2 (M + 1)⁺. 1163-trifluoromethyl- methyl R_(f) = 0.35 (2:1 hexanes/EtOAc); benzylMS(ES) 587.2 (M + 1)⁺. 117 pyridin-2-yl-methyl methyl R_(f) = 0.25 (2:1hexanes/EtOAc); MS(ES) 520.2 (M + 1)⁺. 118 pyridin-4-yl-methyl methylR_(f) = 0.09 (2:1 hexanes/EtOAc); MS(ES) 520.2 (M + 1)⁺. 1191-phenyl-ethyl methyl R_(f) = 0.28 (2:1 hexanes/EtOAc); MS(ES) 533.2(M + 1)⁺. 120 1-(3-chloro-phenyl)- methyl R_(f) = 0.35 (2:1hexanes/EtOAc); ethyl MS(ES) 567.2 (M + 1)⁺. 121 2-chloro-6-fluoro-methyl R_(f) = 0.30 (2:1 hexanes/EtOAc); benzyl MS(ES) 571.2 (M + 1)⁺.122 2,6-dichloro-benzyl methyl R_(f) = 0.35 (2:1 hexanes/EtOAc); MS(ES)587.1 (M + 1)⁺. 123 2,3-dichloro-benzyl methyl R_(f) = 0.33 (2:1hexanes/EtOAc); MS(ES) 587.1 (M + 1)⁺. 124 2-chloro-4-fluoro- methylR_(f) = 0.30 (2:1 hexanes/EtOAc); benzyl MS(ES) 571.2 (M + 1)⁺. 1252,4-difluoro-benzyl methyl R_(f) = 0.23 (2:1 hexanes/EtOAc); MS(ES)555.2 (M + 1)⁺. 126 2,6-difluoro-benzyl methyl R_(f) = 0.28 (2:1hexanes/EtOAc); MS(ES) 555.2 (M + 1)⁺. 127 2-bromo-benzyl methyl R_(f) =0.28 (2:1 hexanes/EtOAc); MS(ES) 597.1 (M+), 599.1 (M + 2)⁺. 1282-trifluoromethoxy- methyl R_(f) = 0.30 (2:1 hexanes/EtOAc); benzylMS(ES) 603.1 (M + 1)⁺. 129 2-chloro-benzyl 2-chloro- R_(f) = 0.23 (2:1hexanes/EtOAc); benzyl MS(ES) 663.1 (M + 1)⁺. 130 2-fluoro-benzyl2-fluoro- R_(f) = 0.47 (2:1 hexanes/EtOAc); benzyl MS(ES) 631.2 (M +1)⁺. 131 2-chloro-benzyl 1-phenyl- R_(f) = 0.53 (2:1 hexanes/EtOAc);ethyl MS(ES) 643.2 (M + 1)⁺. 132 phenyl methyl R_(f) = 0.17 (2:1hexanes/EtOAc); MS(ES) 505.1 (M + 1)⁺. 133 4-methyl-phenyl methyl R_(f)= 0.14 (2:1 hexanes/EtOAc); MS(ES) 519.2 (M + 1)⁺. 134 3-methyl-phenylmethyl R_(f) = 0.17 (2:1 hexanes/EtOAc); MS(ES) 519.2 (M + 1)⁺. 1352-methyl-phenyl methyl R_(f) = 0.26 (2:1 hexanes/EtOAc); MS(ES) 519.2(M + 1)⁺. 136 2-chloro-benzyl 1-phenyl- R_(f) = 0.26 (2:1hexanes/EtOAc); ethyl MS(ES) 643.2 (M + l)⁺. 137 1-(2-methyl- methylR_(f) = 0.33 (2:1 hexanes/EtOAc); phenyl)-ethyl MS(ES) 547.3 (M + 1)⁺.138 1-(3-fluoro-phenyl)- methyl R_(f) = 0.33 (2:1 hexanes/EtOAc); ethylMS(ES) 551.2 (M + 1)⁺. 139 1-(4-fluoro-phenyl)- methyl R_(f) = 0.33 (2:1hexanes/EtOAc); ethyl MS(ES) 551.2 (M + 1)⁺. 140 1-(2,3-dichloro- methylR_(f) = 0.17 (2:1 hexanes/EtOAc); phenyl)-ethyl MS(ES) 601.1 (M + 1)⁺.141 1,2,3,4-tetrahydro- methyl R_(f) = 0.36 (2:1 hexanes/EtOAc);naphthalen-1-yl MS(ES) 559.2 (M + 1)⁺. 142 indan-1-yl methyl R_(f) =0.28 (2:1 hexanes/EtOAc); MS(ES) 545.3 (M + l)⁺. 143 1,2,3,4-tetrahydro-methyl R_(f) = 0.25 (2:1 hexanes/EtOAc); naphthalen-2-yl MS(ES) 559.3(M + 1)⁺. 144 1-naphthalen-2- methyl R_(f) = 0.25 (2:1 hexanes/EtOAc);yl-ethyl MS(ES) 583.2 (M + 1)⁺. 145 2-chloro-benzyl ethyl R_(f) = 0.34(2:1 hexanes/EtOAc); MS(ES) 567.2 (M + 1)⁺. 146 cyclo-propyl 2-chloro-R_(f) = 0.31 (2:1 hexanes/EtOAc); benzyl MS(ES) 579.2 (M + 1)⁺ 1472-chloro-benzyl propyl R_(f) = 0.40 (2:1 hexanes/EtOAc); MS(ES) 581.2(M + 1)⁺. 148 2-chloro-benzyl isopropyl R_(f) = 0.40 (2:1hexanes/EtOAc); MS(ES) 581.2 (M + 1)⁺. 149 naphthalene-2-yl- methylMS(ES) 569.2 (M + 1)⁺. methyl 150 isobutyl methyl R_(f) = 0.29 (2:1hexanes/EtOAc); MS(ES) 485.2 (M + 1). 151 4-hydroxy-phenyl methyl R_(f)= 0.05 (2:1 hexanes/EtOAc); MS(ES) 521.2 (M + 1)⁺. 152 benzyl isopropylR_(f) = 0.31 (2:1 hexanes/EtOAc); MS(ES) 547.2 (M + 1)⁺. 1532,4-difluoro-phenyl methyl MS(ES) 541.1 (M + 1)⁺. 154 3-chloro-phenylmethyl R_(f) = 0.23 (2:1 hexanes/EtOAc); MS(ES) 539.1 (M + 1)⁺. 155cyclohexyl methyl MS(ES) 511.2 (M + 1)⁺. 156 naphthalene-2-yl methylMS(ES) 555.2 (M + 1)⁺. 157 benzyl propyl MS(ES) 547.2 (M + 1)⁺. 1582-(2-chloro-phenyl)- methyl MS(ES) 567.2 (M + 1)⁺. ethyl 1594-chloro-phenyl methyl R_(f) = 0.17 (2:1 hexanes/EtOAc); MS(ES) 539.1(M + 1)⁺. 160 2-methyl-benzyl methyl R_(f) = 0.25 (2:1 hexanes/EtOAc);MS(ES) 533.3 (M + 1)⁺. 161 3,4-dichloro-phenyl methyl R_(f) = 0.24 (2:1hexanes/EtOAc); MS(ES) 573.1 (M + 1)⁺. 162 benzyl ethyl R_(f) = 0.30(2:1 hexanes/EtOAc); MS(ES) 533.2 (M + 1)⁺. 163 4-methoxy-phenyl methylR_(f) = 0.12 (2:1 hexanes/EtOAc); MS(ES) 535.2 (M + 1)⁺. 164 indan-2ylmethyl R_(f) = 0.26 (2:1 hexanes/EtOAc); MS(ES) 545.3 (M + 1)⁺. 165pyridin-2-yl methyl R_(f) = 0.08 (2:1 hexanes/EtOAc); MS(ES) 506.2 (M +1)⁺. 166 6-methyl-pyridin-2- methyl R_(f) = 0.33 (2:1 hexanes/EtOAc);yl-methyl MS(ES) 534.2 (M + 1)⁺. 167 cyclopentyl methyl R_(f) = 0.24(2:1 hexanes/EtOAc); MS(ES) 497.2 (M + 1)⁺. 168 propyl methyl R_(f) =0.22 (2:1 hexanes/EtOAc); MS(ES) 471.1 (M + 1)⁺. 169 2-(2-methoxy-methyl R_(f) = 0.19 (2:1 hexanes/EtOAc); phenyl)- MS(ES) 1-methyl-ethyl170 cyclo-propyl benzyl R_(f) = 0.32 (2:1 hexanes/EtOAc); MS(ES) 545.2(M + 1)⁺ 171 4-trifluoromethoxy- methyl R_(f) = 0.24 (2:1hexanes/EtOAc); phenyl MS(ES) 589.1 (M + 1)⁺. 172 (R)-1-phenyl-ethylmethyl MS(ES) 533.2 (M + 1)⁺. 173 2-diethylamino- methyl R_(f) = 0.07(2:1 hexanes/EtOAc); ethyl MS(ES) 528.3 (M + 1)⁺. 174 2-dimethylamino-methyl R_(f) = 0.09 (2:1 hexanes/EtOAc); ethyl MS(ES) 500.1 (M + 1)⁺.175 3-diethylamino- methyl R_(f) = 0.03 (2:1 hexanes/EtOAc); propylMS(ES) 542.3 (M + 1)⁺. 176 ethyl ethyl R_(f) = 0.22 (2:1 hexanes/EtOAc);MS(ES) 471.1 (M + 1)⁺. 177 (S)-1-phenyl-ethyl methyl MS(ES) 533.2 (M +1)⁺. 178 ethyl methyl R_(f) = 0.16 (2:1 hexanes/EtOAc); MS(ES) 457.1(M + l)⁺. 179 1-benzyl-pyrrolidin- methyl R_(f) = 0.25 (2:1hexanes/EtOAc); 3-yl MS(ES) 588.2 (M + 1)⁺. 180 1-methyl-piperidin-methyl MS(ES) 526.2 (M + l)⁺. 4-yl 181 isopropyl methyl R_(f) = 0.24(2:1 hexanes/EtOAc); MS(ES) 471.2 (M + 1)⁺. 182 1-benzyl-piperidin-methyl R_(f) = 0.32 (2:1 hexanes/EtOAc); 4-yl MS(ES) 602.3 (M + 1)⁺.

By a method similar to Example 100, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # —NR²R³ Data 183 2-phenyl-piperidino R_(f) = 0.39 (2:1hexanes/EtOAc); MS(ES) 559.3 (M + 1)⁺. 184 2-phenyl-pyrrolidin-1-ylR_(f) = 0.11 (2:1 hexanes/EtOAc); MS(ES) 545.3 (M + 1)⁺. 1854,4-dimethyl-2-phenyl- R_(f) = 0.28 (2:1 hexanes/EtOAc); MS(ES)pyrrolidin-1-yl 573.3 (M + 1)⁺. 186 3-phenyl-pyrrolidin-1-yl R_(f) =0.14 (2:1 hexanes/EtOAc); MS(ES) 545.3 (M + 1)⁺. 1873-(2-chloro-phenyl)- R_(f) = 0.15 (2:1 hexanes/EtOAc); MS(ES) piperidino593.3 (M + 1)⁺. 188 3-(3-chloro-phenyl)- R_(f) = 0.21 (2:1hexanes/EtOAc); MS(ES) piperidino 593.3 (M + 1)⁺. 1892,4-diphenyl-pyrrolidin- R_(f) = 0.27 (2:1 hexanes/EtOAc); MS(ES) 1-yl621.3 (M + 1)⁺. 190 3-(3-trifluoromethyl- R_(f) = 0.21 (2:1hexanes/EtOAc); MS(ES) phenyl)-piperidino 627.3 (M + 1)⁺. 1912,2-diphenyl-pyrrolidin- R_(f) = 0.30 (2:1 hexanes/EtOAc); MS(ES) 1-yl621.3 (M + 1)⁺. 192 2-pyridin-3-yl-pyrrolidin- R_(f) = 0.44 (2:1hexanes/EtOAc); MS(ES) 1-yl 546.1 (M + 1)⁺. 193 2-methyl-pyrrolidin-1-ylR_(f) = 0.21 (2:1 hexanes/EtOAc); MS(ES) 483.2 (M + 1)⁺. 194(R)-2-methoxymethyl- R_(f) = 0.12 (2:1 hexanes/EtOAc); MS(ES)pyrrolidin-1-yl 513.2 (M + 1)⁺. 195 (S)-2-pyrrolidin-1- R_(f) = 0.18(2:1 hexanes/EtOAc); MS(ES) ylmethyl-pyrrolidin-1-yl 552.2 (M + 1)⁺. 1962-(2-chloro-phenyl)- R_(f) = 0.18 (2:1 hexanes/EtOAc); MS(ES)thiazolidin-3-yl 597.2 (M + 1)⁺. 197 2-(2-chloro-phenyl)- R_(f) = 0.18(2:1 hexanes/EtOAc); MS(ES) pyrrolidin-1-yl 579.1 (M + 1)⁺. 198(S)-2-methoxymethyl- R_(f) = 0.15 (2:1 hexanes/EtOAc); MS(ES)pyrrolidin-1-yl 513.2 (M + 1)⁺. 199 9-methyl-1,3,4,5- R_(f) = 0.26 (2:1hexanes/EtOAc); MS(ES) tetrahydro- 559.2 (M + 1)⁺. benzo[c]azepin-2-yl200 1,3,4,5-tetrahydro- R_(f) = 0.20 (2:1 hexanes/EtOAc); MS(ES)benzo[d]azepin-2-yl 545.2 (M + 1)⁺. 201 4-benzyl-piperidino R_(f) = 0.26(2:1 hexanes/EtOAc); MS(ES) 573.2 (M + 1)⁺. 202 2-methyl-3,4-dihydro-R_(f) = 0.25 (2:1 hexanes/EtOAc); MS(ES) 2H-quinolin-1-yl 545.1 (M +1)⁺. 203 3,4-dihydro-2H-quinolin- R_(f) = 0.20 (2:1 hexanes/EtOAc);MS(ES) 1-yl 531.1 (M + 1)⁺. 204 4-cyclohexyl-piperazin- R_(f) = 0.25(2:1 hexanes/EtOAc); MS(ES) 1-yl 566.2 (M + 1)⁺. 2054-(4-fluoro-benzyl)- R_(f) = 0.34 (2:1 hexanes/EtOAc); MS(ES)piperazin-1-yl 592.2 (M + 1)⁺. 206 2,3-dihydro-indol-1-yl R_(f) = 0.50(2:1 hexanes/EtOAc); MS(ES) 517.2 (M + 1)⁺. 207 4-(4-fluoro-phenyl)-R_(f) = 0.16 (2:1 hexanes/EtOAc); MS(ES) piperazin-1-yl 578.3 (M + 1)⁺.208 3,4-dihydro-1H- R_(f) = 0.28 (2:1 hexanes/EtOAc); MS(ES)isoquinolin-2-yl 531.0 (M + 1)⁺.

By a method similar to Example 100, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R² R³ Data 209 2,3-dichloro- 4-fluoro-phenyl R_(f) = 0.25 (2:1Hex/EtOAc); benzyl MS(ES) 605.1 (M + 1)⁺. 210 2-bromo-benzyl4-fluoro-phenyl) R_(f) = 0.28 (2:1 Hex/EtOAc); MS(ES) 615.1 (M+), 617.1(M + 2)⁺. 211 2-chloro-4-fluoro- 4-fluoro-phenyl R_(f) = 0.26 (2:1Hex/EtOAc); benzyl MS(ES) 589.2 (M + 1)⁺. 212 2-chloro-6-fluoro-4-fluoro-phenyl R_(f) = 0.36 (2:1 Hex/EtOAc); benzyl MS(ES) 589.1 (M +1)⁺. 213 2-chloro-benzyl 2-fluoro-phenyl R_(f) = 0.29 (2:1 Hex/EtOAc);MS(ES) 571.16 (M + 1)⁺. 214 2-chloro-benzyl 4-methyl-phenyl R_(f) = 0.29(2:1 Hex/EtOAc); MS(ES) 567.18 (M + 1)⁺. 215 2-chloro-benzyl4-methoxy-phenyl R_(f) = 0.26 (2:1 Hex/EtOAc); MS(ES) 583.2 (M + 1)⁺.216 2-chloro-benzyl 2-chloro-phenyl R_(f) = 0.27 (2:1 Hex/EtOAc); MS(ES)587.13 (M + 1)⁺. 217 2-chloro-benzyl 4-chloro-phenyl MS(ES): 587.13 (M +1)⁺ 218 2-chloro-benzyl 3-methyl-phenyl R_(f) = 0.34 (2:1 Hex/EtOAc);MS(ES) 567.2 (M + 1)⁺. 219 2-chloro-benzyl 4-fluoro-phenyl R_(f) = 0.27(2:1 Hex/EtOAc); MS(ES) 571.16 (M + 1)⁺. 220 phenyl 4-fluoro-phenylR_(f) = 0.16 (2:1 Hex/EtOAc); MS(ES) 523.17 (M + 1)⁺. 221 phenyl2-chloro-phenyl R_(f) = 0.17 (2:1 Hex/EtOAc); MS(ES) 539.15 (M + 1)⁺.222 phenyl 3-methoxy-phenyl R_(f) = 0.14 (2:1 Hex/EtOAc); MS(ES) 535.19(M + 1)⁺. 223 2-chloro-benzyl 3-methoxy-phenyl R_(f) = 0.25 (2:1Hex/EtOAc); MS(ES) 583.18 (M + 1)⁺. 224 phenyl 4-methyl-phenyl R_(f) =0.17 (2:1 Hex/EtOAc); MS(ES) 519.2 (M + 1)⁺. 225 phenyl 4-methoxy-phenylR_(f) = 0.11 (2:1 Hex/EtOAc); MS(ES) 535.2 (M + 1)⁺. 226 phenyl4-chloro-phenyl R_(f) = 0.21 (2:1 Hex/EtOAc); MS(ES) 539.15 (M + 1)⁺.227 2-chloro-benzyl 3-trifluoromethyl- R_(f) = 0.33 (2:1 Hex/EtOAc);phenyl MS(ES) 621.17 (M + 1)⁺. 228 phenyl 3-trifluoromethyl- R_(f) =0.19 (2:1 Hex/EtOAc); phenyl MS(ES) 573.18 (M + )⁺. 229 phenyl3-methyl-phenyl R_(f) = 0.19 (2:1 Hex/EtOAc); MS(ES) 519.2 (M + 1)⁺. 230phenyl 2-fluoro-phenyl R_(f) = 0.12 (2:1 Hex/EtOAc); MS(ES) 523.17 (M +1)⁺.

By a method analogous to Example 100, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R^(a) R^(b) Data 231 3,5-dimethoxy hydrogen R_(f) = 0.25 (2:1Hex/EtOAc); MS(ES) 443.2 (M + 1)⁺. 232 3,5-dimethoxy 2-chloro R_(f) =0.32 (2:1 Hex/EtOAc); MS(ES) 477.1 (M + 1)⁺.

EXAMPLE 233 1-(2-Chloro-benzyl)-1H-[1,2,3 ]triazole-4-carboxylic acidbenzyl-methyl-amide

In a screw cap test tube, dissolve1-(2-chloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester(133 mg, 0.5 mmol) in EtOH (0.5 mL), add N-benzyl-N-methylamine (182 mg,1.5 mmol) and NaCN (5 mg, 0.1 mmol). Seal the test tube and heat at 100°C. in a block heater placed on an orbital shaker for agitation. After 12hr, cool to room temp. and add H₂O (5 mL) and extract with EtOAc. Drythe organic layer (MgSO₄), filter, and concentrate. Purify the residueby chromatography on silica gel using a hexane/EtOAc gradient to providethe title compound (101 mg, 59%) as an oil. R_(f)=0.33 (1:1 hex/EtOAc);MS(ES) 341.1 (M+l)⁺.

EXAMPLE 2341-(3,5-Bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acidbenzyl-methyl-amide

Using a procedure analogous to that for Example 233 and using theappropriate starting materials, the title compound was prepared andisolated. R_(f)=0.21 (2:1 hex/EtOAc); MS(ES) 443.2 (M+1)⁺.

EXAMPLE 235 1-Phenethyl-5-phenyl-1H-imidazole-4-carboxylic acid(2-chloro-benzyl)-methyl-amide

Suspend 1-phenethyl-5-phenyl-1H-imidazole-4-carboxylic acid (1.36 g,0.328 mmol) and 1-hydroxybenzotriazole-H₂O (0.89 g, 0.656 mmol) in 3 mLof CH₂Cl₂ at RT. Add 2-chloro-N-methylbenzyl amine (0.131 g, 0.656 mmol)and triethylamine (0.23 mL, 1.64 mmol), then EDCl(0.126 g,0.656 mmol)and stir the resulting orange mixture at RT for 16 h. Dilute with CH₂Cl₂and wash with saturated aqueous NaHCO₃. Dry over MgSO₄, filter, andconcentrate. Purify by chromatography (SiO₂, hexanes/EtOAc gradient toyield 0.044 g (60%) of the title compound. ¹H-NMR is consistent withstructure; MS(ES) 430.1 (M+1)⁺; Anal. Calc'd for C₁₈H₂₆N₂O₄: C, 64.65;H, 7.83; N, 8.34. Found: C, 64.45; H, 7.90; N, 8.38.

By a method analogous to Example 235, using the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # D¹—R¹ R² Data 236 phenethyl 2-bromo- R_(f) = 0.13 (10:1CHCl₃/MeOH); benzyl MS(ES) 474.1 (M+), 476.1 (M + 2)⁺. 237 phenethyl2-methoxy- R_(f) = 0.16 (10:1 CHCl₃/MeOH); benzyl MS(ES) 426.2 (M + 1)⁺238 phenethyl 3,5-bis- R_(f) = 0.22 (10:1 CHCl₃/MeOH); trifluoro- MS(ES)532.2 (M + 1)⁺. methyl- benzyl 239 3,5-bis-trifluoro- 4-chloro- R_(f) =0.17 (10:1 CHCl₃/MeOH); methyl-benzyl benzyl MS(ES) 552.1 (M + 1)⁺. 2403,5-bis-trifluoro- 2-trifluoro- R_(f) = 0.23 (10:1 CHCl₃/MeOH);methyl-benzyl methoxy- MS(ES) 602.2 (M + )⁺. benzyl 2413,5-bis-trifluoro- 4-methoxy- R_(f) = 0.17 (10:1 CHCl₃/MeOH);methyl-benzyl benzyl MS(ES) 548.2 (M + 1)⁺. 242 3,5-bis-trifluoro-phenyl R_(f) = 0.20 (10:1 CHCl₃/MeOH); methyl-benzyl MS(ES) 504.2 (M +1)⁺. 243 3,5-bis-trifluoro- phenethyl R_(f) = 0.13 (10:1 CHCl₃/MeOH);methyl-benzyl MS(ES) 532.2 (M + 1)⁺. 244 3,5-bis-trifluoro- 4-methyl-R_(f) = 0.20 (10:1 CHCl₃/MeOH); methyl-benzyl phenyl MS(ES)) 518.2 (M +1)⁺. 245 3,5-bis-trifluoro- 4-methyl- R_(f) = 0.13 (10:1 CHCl₃/MeOH);methyl-benzyl benzyl MS(ES) 532.2 (M + 1)⁺. 246 3,5-bis-trifluoro-3-methyl- R_(f) = 0.20 (10:1 CHCl₃/MeOH); methyl-benzyl benzyl MS(ES)532.2 (M + 1)⁺. 247 3,5-bis-trifluoro- 2-methyl- R_(f) = 0.17 (10:1CHCl₃/MeOH); methyl-benzyl benzyl MS(ES) 532.3 (M + 1)⁺. 2483,5-bis-trifluoro- 3-methoxy- R_(f) = 0.23 (10:1 CHCl₃/MeOH);methyl-benzyl benzyl MS(ES) 548.3 (M + 1)⁺. 249 3,5-bis-trifluoro-2-bromo- R_(f) = 0.08 (10:1 CHCl₃/MeOH); methyl-benzyl benzyl MS(ES)596.2 (M+), 598.2 (M + 2)⁺. 250 3,5-bis-trifluoro- 2,3-dichloro- MS586.4; MS(ES) methyl-benzyl benzyl 586.2 (M + 1)⁺. 2513,5-bis-trifluoro- 2-methoxy- R_(f) = 0.15 (10:1 CHCl₃/MeOH);methyl-benzyl benzyl MS(ES) 548.3 (M + 1)⁺. 252 3,5-bis-trifluoro-3-chloro- R_(f) = 0.20 (10:1 CHCl₃/MeOH); methyl-benzyl benzyl MS(ES)552.2 (M + 1)⁺. 253 3,5-bis-trifluoro- 4-fluoro- R_(f) = 0.13 (10:1CHCl₃/MeOH); methyl-benzyl benzyl MS(ES) 536.2 (M + 1)⁺. 2543,5-bis-trifluoro- 2-chloro-4- R_(f) = 0.20 (10:1 CHCl₃/MeOH);methyl-benzyl fluoro- MS(ES) 570.2 (M + 1 )⁺. benzyl 2553,5-bis-trifluoro- benzyl R_(f) = 0.20 (10:1 CHCl₃/MeOH); methyl-benzylMS(ES) 518.3 (M + 1)⁺.

EXAMPLE 256[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Using a method analogous to Example 235, the title compound may beprepared and isolated. R_(f)=0.10 (10:1 CHCl₃/MeOH); MS(ES) 578.2 (M+1).

EXAMPLE 2571-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2.75g, 7.36 mmol) in CH₂Cl₂ (60 mL) with(2-chloro-benzyl)-methyl-amine (1.39 g, 8.93 mmol), DMAP (1.18 g, 9.66mmol), and EDCI (1.62 g, 8.45 mmol). Stir at RT for 16 h then heat toreflux for an additional 3 h. Cool back to RT and dilute the solutionwith CH₂Cl₂ (40 mL). Wash with saturated NaHCO₃ (50 mL), H₂O (50 mL),and brine (50 mL), then dry, filter, and concentrate. Purify the crudematerial by flash chromatography, using a linear gradient of 15% to 40%EtOAc/hexanes, to afford the title compound (3.15 g, 84%) as a clearviscous oil. MS(ES) 511.0 (M+1)⁺. ¹H NMR (400 MHz, CHCl₃, mixture ofamide rotamers) δ 7.88 (s, 0.5 H), 7.87 (s, 0.5 H), 7.82 (s, 1 H), 7.76(s, 1 H), 7.20-7.38 (m, 4 H), 5.65 (s, 1 H), 5.61 (s, 1 H), 5.10 (s, 1H), 4.88 (s, 1 H), 3.32 (s, 1.5 H), 3.03 (s, 1.5 H).

EXAMPLE 2581-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-5 chloro-benzyl)-(2-methoxy-ethyl)-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (180 mg, 1 eq), N-(2-chloro-benzyl)-N-(2-methoxy-ethyl)-amine (105mg, 1.5 eq), EDCI (100 mg, 1.1 eq.), HOAt (70 mg, 1.1 eq.), TEA (0.1 mL,1.1 eq.) and DMAP (5 mg) in DMF (5 mL) and stir overnight at RT.Concentrate to dryness then dissolve in 20% iPrOH/CHCl₃ and wash withsaturated aqueous NaHCO₃ and brine. Dry (Na₂SO₄), filter, andconcentrate to dryness. Purify the residue by chromatography on silicagel to provide the title compound (47% yield). MS(ES) 554.9 (M+1)⁺;R_(f)=0.60 (1:1 EtOAc/hexanes).

EXAMPLE 2591-(3,5-Bis-trifluoromethyl-benzyl)-5-phenoxy-1H-[1,2,3]tri-azole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (80 mg, 0.16 mmol) in DMF (1.0 mL)with phenol (56 mg, 0.60 mmol) and Cs₂CO₃ (188 mg, 0.58 mmol) and heatto 70° C. for 18 h. Dilute mixture with H₂O and extract with EtOAc (25mL). Wash the organic phase with 2N Na₂CO₃ (10 mL) and brine (10 mL),then dry, filter, and concentrate. Purify the crude material by flashchromatography, using a linear gradient of 15% to 40% EtOAc/hexanes, togive the title compound (53 mg, 60%) as a yellow viscpous oil. MS(ES)569.2 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃, 1:1 mixture of amide rotamers) δ7.79 (s, 0.5H), 7.76 (s, 0.5H), 7.71 (s, 1H), 7.63 (s, 1H), 6.92-7.35(m, 7H), 6.83 (d, 1H, J=7.4 Hz), 6.78 (d, 1H, J=7.8 Hz), 5.50 (s, 1H),5.42 (s, 1H), 5.17 (s, 1H), 4.70 (s, 1H), 3.27 (s, 1.5H), 2.89 (s,1.5H).

Using a method similar to Example 259, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R⁵ Data 260 4-chloro-phenoxy MS(ES) 603.1 (M + 1)⁺. 2614-methyl-phenoxy MS(ES) 583.2 (M + 1)⁺. 262 3-chloro-phenoxy MS(ES)603.1 (M + 1)⁺. 263 4-methoxy-phenoxy MS(ES) 599.2 (M + 1)⁺. 2643-pyridyloxy MS(ES) 570.1 (M + 1)⁺. 265 2-pyridyloxy MS(ES) 570.0 (M +1)⁺.

EXAMPLE 2661-(3,5-Bis-trifluoromethyl-benzyl)-5-phenylsulfanyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (69 mg, 0.14 mmol) and benzenethiol(20 μL, 0.19 mmol) in DMF (1.3 mL) and stir at RT. After 60 h., dilutethe mixture with H₂O (10 mL) and extract with EtOAc (25 mL). Wash theorganic layer with 2N Na₂CO₃ (10 mL) and brine (10 mL), then dry,filter, and concentrate. Purify crude material by flash chromatographyusing a linear gradient of 15% to 40% EtOAc/hexanes to afford the titlecompound (40 mg, 50%) as a yellow, viscous oil. MS(ES) 585.2 (M+1)⁺; ¹HNMR (400 MHz, CHCl₃1:1 mixture of amide rotamers) δ 7.70 (s, 0.5H), 7.67(s, 0.5H), 7.53 (s, 1H), 7.45 (s, 1H), 7.02-7.36 (m, 9H), 5.65 (s, 1H),5.57 (s, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 3.13 (s, 1.5H), 3.04 (s,1.5H).

Using a method similar to Example 266, with the appropriate startingmaterials, wing compounds may be prepared and isolated.

Ex. # R⁵ Data 267 4-chloro-phenyl-sulfanyl MS(ES) 619.1 (M + 1)⁺. 2683-chloro-phenyl-sulfanyl MS(ES) 619.1 (M + 1)⁺. 2694-methoxy-phenyl-sulfanyl MS(ES) 599.2 (M + 1)⁺. 2703-methyl-phenyl-sulfanyl MS(ES) 615.0 (M + 1)⁺.

EXAMPLE 2711-(3,5-Bis-trifluoromethyl-benzyl)-5-phenylamino-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine a solution of aniline (45 μL, 0.49 mmol) in THF (0.5 mL) withmethyllithium (0.22 mL of a 1.4M soln in ether, 0.31 mmol). Add1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (64 mg, 0.12 mmol) as a solution inTHF (1.0 mL) and stir at RT. After 20 min., dilute with ether (10 mL)and wash the organic solution with saturated aqueous NH₄Cl (2×5 mL) thendry, filter, and concentrate. Purify the crude material by flashchromatography using a linear gradient of 10% to 40% EtOAc/hexanes toafford the title compound (54 mg, 76%) as a red viscous oil. MS(ES)568.2 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃, 1:1 mixture of amide rotamers) δ8.39 (s, 0.5H), 8.32 (s, 0.5H), 7.75 (s, 1H), 7.12-7.38 (m, 9H), 6.80(m, 2H), 5.54 (s, 1H), 5.30 (s, 1H), 5.25 (s, 1H), 4.83 (s, 1H),3.67 (s,1.5H),3.01 (s, 1.5H).

EXAMPLE 2721-(3,5-Bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(2-chloro-benzyl)-methyl-amide

Add EDCI (86 mg, 0.45 mmol) to a solution of(2-chloro-benzyl)-methyl-amine (91 mg, 0.58 mmol),1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(99 mg, 0.29 mmol), and DMAP (89 mg, 0.73 mmol) in CH₂Cl₂ (3.0 mL) andstir at RT. After 24 h., dilute the solution with CH₂Cl₂ (10 mL) andwash with saturated aqueous NH₄Cl (10 mL) and saturated aqueous NaHCO₃(10 mL) then dry, filter and concentrate. Purify the crude material byflash chromatography using a linear gradient of 10% to 40% EtOAcihexanesto afford the title compound (108 mg, 77%) as a white solid. MS(ES)477.0 (M+1)⁺, ¹H NMR (400 MHz, CHCl₃, 1:1 mixture of amide rotamers) δ8.21 (s, 0.5H), 8.16 (s, 0.5H), 7.88 (s, 0.5H), 7.87 (s, 0.5H), 7.81 (s,1H), 7.73 (s, 1H), 7.19-7.37 (m, 4H), 5.66 (s, 1H), 5.63 (s, 1H), 5.39(s, 1H), 4.86 (s, 1H), 3.53 (s, 1.5H), 3.03 (s, 1.5H).

Using a method analogous to Example 272, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R⁵ Data 273 methyl MS(ES) 491.1 (M + 1)⁺. 274 Ethyl MS(ES) 505.2(M + 1)⁺. 275 n-propyl MS(ES) 519.1 (M + 1)⁺. 276 n-butyl MS(ES) 533.1(M + 1)⁺. 277 trifluoromethyl MS(ES) 545.2 (M + 1)⁺.

EXAMPLE 2781-(3,5-Bis-trifluoromethyl-benzyl)-5-butoxy-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-butoxy-1H-[1,2,3)triazole-4-carboxylicacid (42 mg, 0.10 mmol), (2-Chloro-benzyl)-methyl-amine (67 mg, 0.43mmol), and DMAP (69 mg, 0.56 mmol) in CH₂Cl₂ (1.0 mL) with EDCI (54 mg,0.28 mmol) and stir at RT. After 60 h., dilute solution with CH₂Cl₂ (20mL) and wash with aqueous 0.5N HCl (10 mL), H₂O (10 mL), and saturatedNaHCO₃ (10 mL). Dry, filter, and concentrate the organic solution.Purify the crude material by flash chromatography using a lineargradient of 0% to 40% EtOAc/hexanes to afford the title compound (48 mg,86%) as a clear, colorless oil. MS(ES) 549.2 (M+1)⁺; ¹H NMR (400 MHz,CHCl₃, 1:1 mixture of amide rotamers) δ 7.85 (s, 1H), 7.80 (s, 1H), 7.76(s, 1H), 7.20-7.36 (m, 4H), 5.42 (s, 1H), 5.38 (s, 1H), 5.05 (s, 1H),4.86 (s, 1H), 4.38 (q, 2H, J=4.9 Hz), 3.26 (s, 1.5H), 3.00 (s, 1.5H),1.64 (m, 2H), 1.35 (m, 2H), 0.89 (t, 3H, J=7.3 Hz).

EXAMPLE 2795-Benzyloxy-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Using a similar method to Example 278, except using5-benzyloxy-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (61 mg, 0.14 mmol), affords the title compound (30 mg, 37%) as aclear, colorless oil. MS(ES) 583.2 (M+1)⁺. ¹H NMR (400 MHz, CHCl₃, 1:1mixture of amide rotamers) δ 7.85 (s, 0.5H), 7.83 (s, 0.5H), 7.69 (s,1H), 7.64 (s, 1H), 7.18-7.40 (m, 9H), 5.48 (s, 1H), 5.47 (s, 1H), 5.32(s, 1H), 5.26 (s, 1H), 4.95 (s, 1H), 4.8.9 (s, 1H), 3.19 (s, 1.5H), 3.03(s, 1.5H).

EXAMPLE 2801-(3,5-Bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine piperazine (210 mg, 2.44 mmol) with a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (60 mg, 0.12 mmol) in THF (0.50 mL)and heat to 80° C. in a sealed tube. After 16 h, cool the solution to RTand dilute with Et₂O (30 mL). Wash with H₂O (3×10 mL), saturated aqueousNH₄Cl (10 mL), and saturated aqueous NaHCO₃ (10 mL), then dry, filter,and concentrate. Purify crude material by dissolving in methanol (0.5mL) and applying to a Varian SCX column. Elute first with methanol (30mL) to remove unreacted1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]tri-azole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide, then elute with 2M NH₃/MeOH (30 mL)to afford the title compound (50 mg, 76%) as a clear, colorless oil.MS(ES) 561.1 (M+1)⁺, ¹H NMR (400 MHz, CHCl₃, 1:1 mixture of amiderotamers) δ 7.83 (m, 2H), 7.79 (s, 1H), 7.18-7.37 (m, 4H), 5.53 (s, 1H),5.48 (s, 1H), 5.08 (s, 1H), 4.86 (s, 1H), 3.25 (s, 1.5H), 3.02 (s,1.5H), 2.96 (m, 8H), 2.35 (br s, 1H).

Using a method similar to Example 280, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R⁵ Data 281 4-methyl-piperazin-1-yl MS(ES) 575.0 (M + 1)⁺. 2822-dimethlamino-ethylamino MS(ES) 563.2 (M + 1)⁺.

EXAMPLE 2831-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-benzyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (64 mg, 0.12 mmol) in morpholine(0.8 mL) and heat to 80° C. After 16 h, cool to RT and dilute thesolution with EtOAc (25 ml). Wash with saturated aqueous NH₄Cl (2×15mL), H₂O (15 mL), and saturated aqueous NaHCO₃ (15 mL). Dry, filter, andconcentrate, then purify by flash chromatography using a linear gradientof 10% to 40% EtOAc/hexanes to afford the title compound (61 mg, 87%) asa clear, colorless oil. MS(ES) 562.1 (M+1 )⁺; ¹H NMR (400 MHz, CHCl₃,1:1 mixture of amide rotamers) δ 7.85 (s, 0.5H), 7.84 (s, 0.5H), 7.82(s, 1H), 7.77 (s, 1H), 7.18-7.38 (m, 4H), 5.54 (s, 1H), 5.50 (s, 1H),5.08 (s, 1H), 4.88 (s, 1H), 3.72 (m, 4H), 3.25 (s, 1.5H), 3.03 (s,1.5H), 2.99 (m, 4H).

EXAMPLE 2841-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,3]triazole4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add pyrrolidine (17 μL) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3)triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (46 mg, 0.09 mmol) in THF (1.0 mL)and stir at RT in a sealed tube. After 16 h, heat the solution to 80° C.for 24 h, then add additional pyrrolidine (34 μL, 0.18 mmol) and heat to90° C. for and additional 16 h. Cool the solution to RT and dilute withEtOAc (20 mL), then wash with 0.2N HCl (10 mL) and saturated aqueousNaHCO₃ (10 mL). Dry, filter, and concentrate the organic solution, thenpurify crude material by flash chromatography using a linear gradient of15% to 45% EtOAc/hexanes to afford the title compound (31 mg, 63%) as aclear, colorless oil. MS (ES) 546.1 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃, 1:1mixture of amide rotamers) δ 7.83 (s, 0.5H), 7.82 (s, 0.5H), 7.72 (s,1H), 7.68 (s, 1H), 7.18-7.37 (m, 4H), 5.55 (s, 1H), 5.50 (s, 1H), 5.06(s, 1H), 4.86 (s, 1H), 3.24 (s, 1.5H), 3.16 (m, 4H), 3.00 (s, 1.5H),1.92 (m, 4H).

EXAMPLE 2851-(3,5-Bis-trifluoromethyl-benzyl)-5-piperidin-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (52 mg, 0.10 mmol) in piperidine(1.0 mL) and heat to 80° C. for 16 h in a sealed tube. Cool to RT anddilute with EtOAc (50 mL). Wash organic solution with 1N HCl (10 mL),H₂O (10 mL), and saturated aqueous NaHCO₃ (10 mL) then dry, filter, andconcentrate. Purify crude material by flash chromatography using alinear gradient of 10% to 40% EtOAc to afford the title compound (57 mg,100%) as a clear, colorless oil. MS(ES) 560.1 (M+1)⁺, ¹H NMR (400 MHz,CHCl₃, 1:1 mixture of amide rotamers) δ 7.84 (m, 2H), 7.79 (s, 1H),7.17-7.37 (m, 4H), 5.49 (s, 1H), 5.45 (s, 1H), 5.06 (s, 1H), 4.87 (s,1H), 3.23 (s, 1.5H), 3.02 (s, 1.5H), 2.92 (m, 4H), 1.92 (m, 6H).

EXAMPLE 2861-(3,5-Bis-trifluoromethyl-benzyl)-5-dimethylamino-1H-[1,2,3)triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add dimethylamine (4.0 mL, 2M in MeOH) to1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (80.0 mg, 0.16 mmol) and heat at100° C. for 16 h in a sealed tube. Concentrate the reaction mixture andpurify by flash chromatography using a linear gradient of 10 to 40%EtOAc in hexanes to afford the title compound (50 mg, 62%) as a clearcolorless oil. MS(ES) 520.27 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1 mixtureof amide rotamers) δ 7.85 (m, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.20-7.40(m, 4H), 5.53 (s, 1H), 5.49 (s, 1H), 5.13 (s,1H), 4.89 (s, 1H), 3.30 (s,1.5H), 3.05 (s, 1.5H), 2.74 (s, 3H), 2.72 (s, 3H).

Using a method analogous to the above example, with the appropriatestarting materials, the following compounds may be prepared andisolated.

Ex. # R⁵ Data 287 diethylamino MS(ES) 548.1 (M + 1)⁺ 288 ethylaminoMS(ES) 520.1 (M + 1)⁺

EXAMPLE 2891-(3,5)-Bis-trifluoromethyl-benzyl)-5-isopropylamino-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add 2M solution of isopropylamine in MeOH (10.0 mL, 20.0 mmol) to1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (0.05 g, 0.10 mmoL) and heat at 100°C. for 16 h in a sealed tube. Concentrate the reaction mixture andpurify by flash chromatography using a linear gradient of 10 to 40%EtOAc in hexane to give the title compound (0.04 g, 86%). MS(ES) 534.1(M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1 mixture of amide rotamers) δ 7.87(s, 0.5H), 7.86 (s, 0.5H), 7.71 (s, 1H), 7.65 (s, 1H), 7.37 (m, 1H),7.23 (m, 3H), 6.50 (brs, 1H), 5.56 (m, 3H), 4.86 (s, 1H), 3.65 (s,1.5H), 3.39 (m, 1H), 3.03 (s, 1.5H), 1.13 (m, 6H).

Using a method analogous to the above example, with the appropriatestarting materials, the following compounds may be prepared andisolated.

Ex. # R⁵ Data 290 2-methoxy-ethylamino MS(ES) 550.0 (M + 1)⁺ 291methylamino MS(ES) 506.0 (M + 1)⁺ 292 thiomorpholin-4-yl MS(ES) 578.0(M + 1)⁺ 293 propylamino MS(ES) 534.1 (M + 1)⁺ 294 azepan-1-yl MS(ES)574.4 (M + 1)⁺ 295 azetidin-1yl MS(ES) 532.3 (M + 1)⁺ 296cyclopropylamino MS(ES) 532.1 (M + 1)⁺ 297 4-hydroxy-piperidino MS(ES)576.5 (M + 1)⁺

EXAMPLE 2985-(4-Acetyl-piperazin-1-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add acetyl chloride (0.1 mL, 1.3 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (0.05 g, 0.10 mmol) andtriethylamine (2.0 mL, 1.4 mmol) in dichloromethane (4.0 mL). Stir at RTfor 4 h, dilute with water and extract with dichloromethane. Washorganic extract with 1N HCl, water, and brine, then dry and concentrate.Purify by flash chromatography using a linear gradient of 1 to 2% MeOHin dichloromethane to give the title compound (0.05 g, 94%). MS(ES)603.1 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃. 1:1 mixture of amide rotamers) δ7.88 (s, 0.5H), 7.87 (s, 0.5H), 7.83 (s, 1H), 7.78 (s, 1H), 7.39 (m,0.5H), 7.33 (m, 0.5H), 7.28 (m, 1H), 7.23 (m, 2H), 5.57 (s, 1H), 5.53(s, 1H), 5.13 (s, 1H), 4.87 (s, 1H), 3.66 (m, 2H), 3.48 (m, 2H), 3.30(s, 1.5H), 2.95-3.05 (s, 5.5H), 2.10 (s, 1.5H), 2.08 (s, 1.5H).

EXAMPLE 2991-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxo-1λ⁴-thiomorpholin-4-yl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add 30% aqueous hydrogen peroxide (10.0 uL, 0.1 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (0.05 g, 0.1 mmol) in MeOH (2.0 mL)and stir at RT for 24 h. Add water and extract with EtOAc, then dry,filter, and concentrate. Purify by flash chromatography using a lineargradient of 3 to 5% MeOH in dichloromethane to give the title compound(0.05 g, 95%). MS(ES) 594.2 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, 1:1 mixtureof amide rotamers) δ 7.89 (s, 0.5H), 7.88 (s, 0.5H), 7.82 (s, 1H), 7.77(s, 1H), 7.39 (m, 0.5H), 7.28-7.35 (m, 1.5H), 7.23 (m, 2H), 5.57 (s,1H), 5.53 (s, 1H), 5.15 (s, 1H), 4.89 (s, 1H), 3.63 (m, 2H), 3.32 (s,1.5H), 3.18 (m, 2H), 3.04 (m, 3.5H), 2.87 (m, 2H).

EXAMPLE 3001-(3,5-Bis-trifluoromethyl-benzyl)-5-propoxy-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Combine EDC.HCl (0.18 g, 0.94 mmol) with a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-propoxy-1H-[1,2,3]triazole-4-carboxylicacid (0.25 g, 0.63 mmol), (2-chloro-benzyl)-methyl-amine (0.18 g, 1.16mmol), and DMAP (0.12 g, 0.94 mmol) in dichloromethane (10.0 mL) andstir mixture for 48 h. Add saturated NaHCO₃ and extract mixture withdichloromethane. Wash the organic layer with water and brine, then dry,concentrate, and purify by flash chromatography using a linear gradientof 10 to 40% EtOAc in hexane to give the title compound (0.30 g, 90%).MS(ES) 535.0 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, 1:1 mixture of amiderotamers) δ 7.89 (s, 0.5H), 7.88 (s, 0.5H), 7.82 (s, 1H), 7.77 (s, 1H),7.39 (m, 0.5H), 7.28-7.35 (m, 1.5H), 7.23 (m, 2H), 5.44 (s, 1H), 5.40(s, 1H), 5.06 (s, 1H), 4.87 (s, 1H), 4.34 (q, 2H, J=6.8), 3.27 (s,1.5H), 3.01 (s, 1.5H), 1.72 (m, 2H), 0.94 (t, 3H, J=6.8).

Using a method similar to the above example, with the appropriatestarting materials, the following compounds may be prepared andisolated.

Ex. # R⁵ Data 301 Ethoxy MS(ES) 521.2 (M + 1)⁺ 302 Methoxy MS(ES) 507.3(M + 1)⁺

EXAMPLE 303 1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-1H-[1,2,3]triazole-4-carboxylic acid(2-chloro-benzyl)-methyl-amide

Add 30% aqueous hydrogen peroxide (20.0 μL, 0.2 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (0.05 g, 0.1 mmol) in MeOH (3.0 mL)and stir at reflux for 24 h. Add water and extract with EtOAc, then dry,filter, and concentrate. Purify by flash chromatography using a lineargradient of 60 to 80% EtOAc in hexane to give the title compound (0.03g, 60%). MS(ES) 609.9 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1 mixture ofamide rotamers) δ 7.91 (s, 0.5H), 7.90 (s, 0.5H), 7.79 (s, 1H), 7.74 (s,1H), 7.35 (m, 1H), 7.30 (m, 0.5H), 7.23 (m, 2.5H), 5.57 (s, 1H), 5.53(s, 1H), 5.18 (s, 1H), 4.91 (s, 1H), 3.52 (m, 4H), 3.35 (s, 1.5H), 3.13(m, 4H), 3.06 (m, 1.5H).

EXAMPLE 3045-Chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(2-chloro-benzyl)-isopropyl-amide

Combine (2-chloro-benzyl)-isopropyl-amine (240 mg, 1.31 mmol) with5-chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylic acid(400 mg, 1.31 mmol), EDCI (250 mg, 1.30 mmol), HOAt (178 mg, 1.31 mmol),and DIEA (0.20 mL, 1.15 mmol), in DMF (8 mL) and stir the mixture at RT.After 72 h, concentrate the mixture in vacuo and partition the residuebetween water and EtOAc. Dry the combined extracts over sodium sulfateand concentrate in vacuo. Purify the residue by chromatography oversilica gel using a MeOH/CH₂Cl₂ gradient to isolate pure product (103 mg,17%) as a white solid. R_(f)=0.19 (CH₂Cl₂); MS(ES) 571.0 (M+1)⁺.

EXAMPLE 3051-(3,5-dichloro-benzyl)-5-morpholin-4yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-isopropyl-amide

Combine 5-chloro-1-(3,5-dichloro-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-isopropyl-amide (75 mg, 0. 16 mmol) withmorpholine (2 mL) and heat the mixture at 100° C. overnight under N₂.Concentrate the mixture in vacuo, then dissolve in EtOAc and wash withwater. Dry over sodium sulfate and concentrate in vacuo. Purify theresidue by chromatography over silica gel using a MeOH/CH₂Cl₂ gradientto isolate pure product (38 mg, 46%). MS(ES) 522.1 (M+1); R_(f)=0.03(CH₂Cl₂).

EXAMPLE 3061-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid isopropyl-(2-methoxy-5-trifluoromethoxy-benzyl)-amide

Combine isopropyl-(2-methoxy-5-trifluoromethoxy-benzyl)-amine (126 mg,0.48 mmol) with1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (200 mg, 0.48 mmol), EDCI (92 mg, 0.48 mmol), HOAt (65 mg, 0.48mmol), and DIEA (0.10 mL, 0.57 mmol), in DMF (5 mL) and stir the mixtureat RT. After 72 h, concentrate the mixture in vacuo, dissolve theresidue in EtOAc and wash with water. Dry over sodium sulfate andconcentrate in vacuo. Purify the residue by chromatography over silicagel using a MeOH/CH₂Cl₂ gradient to isolate the title compound (300 mg,94%) as a thick oil. MS(ES) 662.18 (M+1)⁺.

EXAMPLE 3071-(2-methoxy-5-trifluoromethoxy-benzyl)-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-isopropyl-amide

Combine (2-chloro-benzyl)-isopropyl-amine (138 mg, 0.75 mmol)1-(2-methoxy-5-trifluoromethoxy-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (295 mg, 0.75 mmol), EDCI (144 mg, 0.75 mmol), HOAt (102 mg, 0.75mmol), and DIEA (0.10 mL, 0.57 mmol), in DMF (5 mL) and stir the mixtureovernight at RT. Concentrate the mixture in vacuo and partition theresidue between water and EtOAc. Dry the combined extracts over sodiumsulfate and concentrate in vacuo. Chromatograph the residue over silicagel using MeOH/CH₂Cl₂ to isolate product (294 mg, 70%) as a thick oilwhich solidifies upon standing. ES(MS) 560.2 (M+1)⁺.

EXAMPLE 3081-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrazol-1-yl-1H[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add sodium hydride (17 mg, 0.43 mmol) to pyrazole (30 mg, 0.44 mmol), inTHF (4.0 mL) at RT and stir under nitrogen. After 30 min., add1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide (230 mg, 0.45 mmol) and stir foranother 6-24h. Treat the reaction mixture with water and extract twotimes with ethyl acetate. Combine the organic layers and wash with waterand brine; then dry (Na₂SO₄), filter, and concentrate under reducedpressure. Purification by flash chromatography, eluting with a lineargradient of 15% to 40% ethyl acetate in hexanes gives the title compound(140 mg, 60%). MS(ES) 543.3 (M+1)⁺; ¹H NMR (400 MHz, CHCl₃, 1:1 mixtureof amide rotarmers) δ 8.17 (dd, 1H, J=7.7, 3.0), 7.87 (dd, 1H, J=5.1,1.7), 7.80 (d, 1H, J=5.1), 7.65 (s, 1H), 7.61 (s, 1H), 7.20-7.38 (m,4H), 6.46 (m, 1H), 5.88 (s, 1H), 5.85 (s, 1H), 4.98 (s, 1H), 4.84 (s,1H), 3.23 (s, 1.5H), 2.98 (s, 1.5H).

Using a method analogous to Example 308, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R⁵ Data 309 pyrrol-1-yl MS(ES) 542.3 (M+1)⁺ 310 imidazol-1-ylMS(ES) 543.5 (M+1)⁺

Using a method analogous to Example 308, with the appropriate startingmaterials, the following compounds may be prepared and isolated.

Ex. # R⁵ Data 311 pyrazol-1-yl MS(ES) 569.3 (M+1)⁺ 312 imidazol-1-ylMS(ES) 569.3 (M+1)⁺

EXAMPLE 313[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyrrol-1-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Combine EDCI (132 mg, 0.69 mmol) with a solution of2-(2-chloro-phenyl)-pyrrolidine (125 mg, 0.69 mmol),1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrrol-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (200 mg, 0.50 mmol), and DMAP (85 mg, 0.69 mmol) in CH₂Cl₂ (10.0mL) and stir at RT. After 24 h, dilute the solution with CH₂Cl₂, washwith saturated aqueous NH₄Cl, saturated aqueous NaHCO₃, and water, thendry, filter, and concentrate the organic phase. Purification by flashchromatography eluting with a linear gradient of 15% to 30% EtOAc inhexanes gives the title compound in quantitative yield. MS(ES) 568.3.0(M+1)⁺; ¹H NMR (400 MHz, CHCl₃, 1:1 mixture of amide rotamers) δ 7.82(s, 0.5H), 7.79 (s, 0.5H), 7.48 (s, 1H), 7.35 (s, 1H), 7.30 (m, 0.5H),7.21 (m, 0.5H), 7.13 (m, 1H), 7.03 (m, 1H), 6.94 (m, 0.5H), 6.69 (t, 1H,J=2.2), 6.43 (t, 1H, J=2.2), 6.37 (t, 1H, J=2.2), 6.34 (t, 1H, J=2.2),6.19 (dd, 0.5H, J=7.9, 2.9), 5.6 (dd, 0.5H, J=7.9, 4.0), 5.48 (m, 1H),5.28 (m, 1H), 4.41 (m, 0.5H), 3.95 (m, 1H), 3.83 (m, 1H), 2.32-2.52 (m1H), 1.82-2.01 (m, 3H).

Using a method similar to the above method, with the appropriatestarting materials, the following compounds may be prepared andisolated. DMF may be used as a solvent instead of CH₂Cl₂.

Ex. # R⁵ Data 314 1-methyl-1H-pyrrol-2-yl MS(ES) 582.3 (M+1)⁺ 315pyrazin-2-yl MS(ES) 581.1 (M+1)⁺ 316 pyrimidin-5-yl MS(ES) 581.2 (M+1)⁺317 4-methylsulfanyl-phenyl MS(EI) 625.1 (M+1)⁺

EXAMPLE 318[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(4-methanesulfinyl-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Add[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-methylsulfanyl-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(160 mg, 0.26 mmol) to hydrogen peroxide (0.05 mL of 30% aqueoussolution, 0.52 mmol) in MeOH (1.0 mL) and stir at RT. After 18 h, quenchwith a saturated aqueous solution of NaHSO₃, and concentrate underreduced pressure. Purify the residue by flash chromatography, elutingwith a linear gradient of 60% to 80% EtOAc in hexanes gives the titlecompound in quantitative yield. MS(EI) 64 1.0 (M⁺); ¹H NMR (400 MHz,CDCl₃, 1:1 mixture of amide rotamers.) δ, 7.80 (s, 0.5H), 7.76 (s,0.5H), 7.67 (m, 2H), 7.44 (s, 1H), 7.41 (s, 1H), 7.27 (m, 1H), 7.18 (m,2H), 7.12 (m, 1H), 7.01 (m, 1H), 6.91 (m, 0.5H), 6.26 (m, 0.5H), 5.56(m, 1H), 5.37 (m, 1H), 4.52 (m, 0.5H), 4.09 (m, 0.5H), 3.78-3.89 (m,1H), 2.75 (s, 1.5H), 2.72 (s, 1.5H), 2.45 (m, 1H), 1.85-1.98 (m, 3H).

EXAMPLE 319[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(4-methanesulfonyl-phenyl)-1H-[1,2,3)triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Add 3-chloroperoxybenzoic acid (I0.r mg, 0.45 mmol) to a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-methylsulfanyl-phenyl)-1H-[1,2,3]triazol4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone (134 mg,0.21 mmol) in CH₂Cl₂ (3 mL) and stir at RT for 1-3 h. Treat the reactionmixture with 1N HCl and extract with CH₂Cl₂. Combine the organic layersand wash with water, brine, dry (Na₂SO₄), filter, and concentrate underreduced pressure. Add hexane to the residue, collect the precipitate,and dry under vacuum to give the title compound as a white powder inquantitative yield. MS(ES)657.4 (M⁺). ¹H NMR (400 MHz, CDCl₃) δ, 7.96(s, 1H), 7.94 (s, 1H), 7.82 (s, 0.5H), 7.78 (s, 0.5H), 7.48 (s, 1H),7.45 (m, 1H), 7.32 (s, 1H), 7.25 (m, 2H), 7.16 (m, 1H), 7.11 (m, 0.5H),7.01 (m, 1H), 6.91 (m, 0.5H), 6.28 (dd, 0.5H, J=7.9, 2.6), 5.56 (m,1.5H), 5.36 (m, 1H), 4.53 (m, 0.5H), 4.13 (m, 0.5H), 3.78-3.19 (m, 1H),3.07 (s, 1.5H), 3.03 (s, 1.5H), 2.45 (m, 1H), 1.85-1.98 (m, 3H).

EXAMPLE 3201-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide

Add (2-chloro-benzyl)-methyl-amine (104 mg, 0.67 mmol), DMAP (62 mg,0.51 mmol), and EDCI (81 mg, 0.42 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazole-4-carboxylicacid (104 mg, 0.25 mmol) in CH₂Cl₂ (2.5 mL) and stir the solution at RTfor 60 h. Dilute the solution with CH₂Cl₂ (25 mL) and wash withsaturated aqueous NH₄Cl (10 mL), H₂O (10 mL), and saturated aqueousNaHCO₃ (10 mL). Dry, filter, and concentrate the organic phase, thenpurify by flash chromatography using a linear gradient of 20% to 40%EtOAc/hexanes to give the title compound (125 mg, 90%) as a clear,colorless oil. MS(ES) 554.2 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1 mixtureof amide rotamers) δ 8.71 (m, 1H), 7.89 (m, 1H), 7.76 (m, 2H), 7.74 (s,1H) 7.69 (s, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.21 (m, 1H), 7.14 (m,1H), 6.05 (s, 1H), 6.00 (s, 1H), 4.89 (s, 1H), 4.87 (s, 1H), 3.10 (s,1.5H), 3.03 (s, 1.5H).

Using a method similar to the above method, with the appropriatestarting carboxylic acid, the following compounds may be prepared andisolated.

Ex. # R⁵ Data 321 pyridin-3-yl MS(ES) 554.2 (M+1)⁺; ¹H NMR (400 MHz,CDCl₃, 1:1 mixture of amide rotamers) δ 8.74 (m, 1H), 8.55 (s, 0.5H),8.46 (s, 0.5H), 7.82 (s, 0.5H), 7.81 (s, 0.5H), 7.67 (m, 0.5H), 7.64 (m,0.5H), 7.47 (s, 1H), 7.42 (s, 1H), 7.39 (s, 0.5H), 7.35 (m, 1.5H), 7.22(m, 3H), 5.60 (s, 1H), 5.54 (s, 1H), 5.14 (s, 1H), 4.81 (s, 1H), 3.33(s, 1,5H), 2.97 (s, 1.5H). 322 pyridin-4-yl MS(ES) 554.2 (M+1)⁺; ¹H NMR(400 MHz, CDCl₃, 1:1 mixture of amide rotamers.): δ 8.74 (m, 2H), 7.84(m, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.34 (m, 1H), 7.22 (m, 5H), 5.58(s, 1H), 5.52 (s, 1H), 5.11 (s, 1H), 4.81 (s, 1H), 3.30 (s, 1,5H), 2.98(s, 1.5H). 323 furan-2-yl MS(ES) 543.3 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃,1:1 mixture of amide rotamers.) δ 7.81 (s, 0.5H), 7.79 (s, 0.5H), 7.71(s, 1H) 7.66 (s, 1H), 7.57 (m, 1H), 7.30 (m, 2H), 7.22 (m, 1H), 7.17 (m,2H), 6.54 (m, 1H), 5.91 (s, 1H), 5.86 (s, 1H), 4.88 (s, 2H), 3.15 (s,1,5H), 3.02 (s, 1.5H). 324 furan-3-yl MS(ES) 543.3 (M+1)⁺; ¹H NMR (400MHz, CDCl₃): δ 7.83 (s, 0.5H), 7.81 (s, 0.5H), 7.75 (s, 0.5H) 7.71 (s,0.5H), 7.60 (m, 1H), 7.54 (m, 2H), 7.16-7.36 (m, 4H), 6.43 (m, 1H), 5.66(s, 1H), 5.60 (s, 1H), 4.96 (s, 1H), 4.84 (s, 1H), 3.19 (s, 1,5H), 2.99(s, 1.5H). 325 thiophen-2- MS(ES) 559.2 (M+1)⁺; ¹H NMR (400 MHz, ylCDCl₃): δ 7.81 (s, 0.5H), 7.79 (s, 0.5H), 7.56 (m, 1H) 7.55 (s, 1H),7.49 (s, 1H), 7.32 (m, 1H), 7.17 (m, 5H), 5.67 (s, 1H), 5.62 (s, 1H),4.95 (s, 1H), 4.83 (s, 1H), 3.15 (s, 1,5H), 2.98 (s, 1.5H). 3265-methyl- MS(ES) 573.3 (M+1)⁺; ¹H NMR (400 MHz, thiophen-2- CDCl₃): δ7.81 (s, 0.5H), 7.79 (s, 0.5H), 7.55 (s, yl 1H) 7.50 (s, 1H), 7.32 (m,1H), 7.24 (m, 1H), 7.19 (m, 2H), 6.94 (dd, 1H, J = 3.4, 14.7), 6.78 (m,1H), 5.67 (s, 1H), 5.60 (s, 1H), 4.95 (s, 1H), 4.84 (s, 1H), 3.15 (s,1,5H), 2.98 (s, 1.5H), 2.50 (s, 3H).

EXAMPLE 327(±)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazol-4-yl)-[-]2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-2-yl-1H-[1,2,3]triazole4-carboxylicacid (413 mg, 0.99 mmol), (±)-2-(2-chloro-phenyl)-pyrrolidine (196 mg,1.08 mmol), and DMAP (250 mg, 2.05 mmol) in CH₂Cl₂ (4.0 mL) and treatwith EDCI (248 mg, 1.29 mmol). Stir the solution at RT for 60 h, thendilute with additional CH₂Cl2 (20 mL) and wash with saturated NH₄Cl (10mL), H₂O (10 mL), and saturated NaHCO₃ (10 mL). Dry, filter, andconcentrate the organic phase. Purify the crude material by flashchromatography using a linear gradient of 15% to 40% EtOAc/hexanes togive the title compound (463 mg, 81%) as a white foam. MS(ES) 580.2(M+1)⁺. ¹H NMR (400MHz, CDCl₃): δ 8.68 (d, 0.5H, J=4.9), 8.57 (d, 0.5H,J=4.9), 7.90 (d, 0.5H, J=7.8), 7.80 (d, 0.5H, J=8.3), 7.66-7.74 (m, 5H),7.11-7.34 (m, 3H), 6.67-6.95 (m, 2H), 5.97 (m, 1H), 5.88 (m, 0.5H), 5.78(m, 1H), 5.59 (m, 0.5H), 4.29 (m, 0.5H), 3.92 (m, 1.5H), 2.43 (m, 1H),1.92 (m, 3H).

Using a method similar to the above method, with the appropriatestarting carboxylic acid and (+)-(2R)-2-(2-chloro-phenyl)-pyrrolidine,the following compounds may be prepared and isolated.

Ex. # R⁵ Data 328 pyridin-3-yl MS(ES) 580.3 (M+1)⁺; ¹H NMR (400 MHz,CDCl₃, 1:1 mixture of amide rotamers): δ 8.67 (m, 1H), 8.51 (d, 0.5H, J= 2.0), 8.17 (d, 0.5H, J = 2.0), 7.80 (s, 0.5H), 7.77 (s, 0.5H), 7.63(m, 0.5H), 7.51 (m, 0.5H), 7.44 (s, 1H), 6.86-7.37 (m, 6H), 6.28 (m,0.5H), 5.58 (d, 1H, J = 9.3), 5.55(m, 0.5H), 5.38 (s, 1H), 4.53 (m,0.5H), 4.10 (m, 0.5H), 3.88 (m, 0.5H), 3.81 (m, 0.5H), 2.49 (m, 0.5H),2.39 (m, 0.5H), 1.83-2.00 (m, 3H). 329 pyridin-4-yl MS(ES) 580.2 (M+1)⁺;¹H NMR (400 MHz, CDCl₃, mixture of amide rotamers): δ 8.67 (m, 2H), 7.83(s, 0.5H), 7.80 (s, 0.5H), 7.50 (s, 1H), 7.36 (s, 1H), 6.88-7.36 (m,6H), 6.24 (m, 0.5H), 5.53 (m, 1.5H), 5.35(m, 1H), 4.51 (m, 0.5H), 4.09(m, 0.5H), 3.85 (m, 1H), 2.38-2.49 (m, 1H), 1.89-2.05 (m, 3H). 330pyridazin-4- MS(ES) 581.3 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, yl 1:1 mixtureof amide rotamers) δ 9.22 (dd, 0.5H, J = 1.4, 5.4), 9.18 (dd, 0.5H, J =1.0, 5.4), 9.02(m, 0.5H), 8.73 (m, 0.5H), 7.84 (s, 0.5H), 7.81 (s,0.5H), 7.52 (s, 1H), 7.43 (dd, 0.5H, J = 2.4, 5.4), 7.38 (s, 1H), 7.34(dd, 0.5H, J = 2.4, 5.4), 7.28 (m, 0.5H), 7.22 (m, 0.5H), 7.13 (m,1.5H), 7.04 (dt, 0.5H, J = 1.4, 6.0), 6.97 (dt, 0.5H, J = 1.4, 6.0),6.85 (dd, 0.5H, J = 1.7, 7.8), 6.25 (dd, 0.5H, J = 3.1, 8.3), 5.59 (m,1H), 5.53 (dd, 0.5H, J = 4.0, 8.1), 5.41 (m, 1H), 4.54 (m, 0.5H), 4.13(m, 0.5H), 3.84 (m, 1H), 2.42 (m, 1H), 1.99 (m, 2.5H), 1.87 (m, 0.5H).331 furan-2-yl MS(ES) 569.3 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, mixture ofamide rotamers) δ 7.79 (m, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.54 (s,0.5H), 7.49 (m, 0.5H), 7.33 (m, 0.5H), 7.26 (s, 1.5H), 7.15 (m, 1.5H),6.99 (m, 0.5H), 6.84 (m, 1H), 6.49 (m, 1H), 5.96 (m, 0.5H), 5.90 (s,1H), 5.63 (m, 1.5H), 4.32 (m, 0.5H), 3.92 (m, 1.5H), 2.45 (m, 1H), 1.94(m, 3H). 332 thiophen-2- MS(ES) 585.2 (M+1)⁺. ¹H NMR (400 MHz, ylCDCl₃): δ 7.80 (s, 0.5H), 7.77 (s, 0.5H), 7.52 (s, 1H), 7.51 (m, 1H),7.39 (s, 1H), 7.29 (m, 0.5H), 7.16 (s, 2H), 7.09 (m, 1.5H), 6.95 (m,2H), 6.11 (m, 0.5H), 5.64 (s, 1H), 5.59 (m, 0.5H), 5.43 (m, 1H), 4.37(m, 0.5H), 3.89 (m, 1.5H), 2.43 (m, 1H), 1.92 (m, 3H). 333 5-methyl-MS(ES) 599.3 (M+1)⁺. ¹NMR (400 MHz, CDCl₃): thiophen-2- δ 7.80 (s,0.5H), 7.77 (s, 0.5H), 7.53 (s, 1H), 7.40 yl (m, 1H), 7.29 (m, 0.5H),7.14 (m, 2H), 6.95 (m, 2H), 6.73 (m, 1.5H), 6.13 (dd, 0.5H, J = 3.4,7.8), 5.64 (s, 1H), 5.60 (dd, 0.5H, J = 3.4, 7.8), 5.42 (m, 1H), 4.36(m, 0.5H), 3.91 (m, 1.5H), 2.46 (d, 3H, J = 5.4), 2.43 (m, 1H), 1.93 (m,3H). 334 chloro MS(ES) 537.0 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.88 (s,0.5H), 7.84 (s, 0.5H), 7.80 (s, 1H), 7.64 (s, 1H), 7.33 (m, 0.5H), 7.16(m, 2H), 7.00 (m, 1.5H), 6.23 (m, 0.5H), 5.64 (m, 1.5H), 5.46 (s, 1H),4.44 (m, 0.5H), 4.12 (m, 0.5H), 4.01 (m, 0.5H), 3.87 (m, 0.5H), 2.43 (m,1H), 2.00 (m, 2H), 1.88 (m, 1H). 335 isopropyl ¹H NMR (400 MHz, CDCl₃) δ7.85 (s, 0.5H), 7.80 (s, 0.5H), 7.61 (s, 1H), 7.44 (s, 1H), 7.33 (m,0.5H), 7.24 (m, 0.5H), 7.10-7.20 (m, 1.5H), 6.98-7.04 (m, 1.5H), 6.34(m, 0.5H), 5.66 (s, 1H), 5.64 (m, 0.5H), 5.48 (m, 1H), 4.28 (m, 0.5H),3.85-4.03 (m, 1.5H), 3.33 (m, 0.5H), 3.09 (m, 0.5H), 2.40-2.56 (m, 1H),1.96 (m, 3H), 1.08-1.22 (m, 6H).

EXAMPLE 336(±)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-furan-3-yl-1H-[1,2,3]triazol-4-yl]-[2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Using a method similar to Example 327, with the appropriate startingcarboxylic acid, the title compound may be prepared and isolated. MS(ES)569.3 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 0.5H), 7.80 (s, 0.5H),7.73 (m, 0.5H), 7.59 (s, 1H), 7.50 (m, 1.5H), 7.45 (m, 1H), 7.32 (m,0.5H), 7.22 (s, 0.5H), 7.15 (m, 1.5H), 6.95 (m, 1.5H), 6.42 (m, 0.5H),6.20 (m, 0.5H), 6.13 (m, 0.5H), 5.64 (s, 1H), 5.61 (m, 0.5H), 5.41 (m,1H), 4.42 (m, 0.5H), 3.93 (m, 1.5H), 2.44 (m, 1H), 1.94 (m, 3H).

EXAMPLE 337(+)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Heat a solution of(+)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(1.10 g, 2.05 mmol) in morpholine (20 mL) to 110° C. for 18 h. Cool toRT and dilute with EtOAc (60 mL) then wash with 2.5N HCl (2×50 mL), H₂O(50 mL), and saturated NaHCO₃ (50 mL). Dry, filter, and concentrate theorganic phase. Purify the crude material by flash chromatography using alinear gradient of 10% to 40% EtOAc/hexanes to give(+)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(1.20 g, 99%) as a white foam. [α]_(D)=+43.1 (c=1.02, MeOH). ¹H NMR (400MHz, CDCl₃, mixture of amide rotamers) δ 7.85 (s, 0.5H), 7.83 (s, 1H),7.81 (s, 0.5H), 7.65 (s, 1H), 7.34 (m, 0.5H), 7.16 (m, 2H), 7.96 (m,1.5H), 6.31 (m, 0.5H), 5.64 (m, 0.5H), 5.54 (s, 1H), 5.36 (d, 1H,J=3.4), 4.37 (m, 0.5H), 3.99 (m, 1H), 3.90 (m, 0.5H), 3.59-3.73 (m, 4H),2.87-2.98 (m, 3H), 2.74 (m, 1H), 2.46 (m, 1H), 1.96 (m, 3H). Analytical(C₂₆H₂₄ClF₆N₅O₂): Calculated C, 53.11;H, 4.11; N, 11.91. Found C,53.41;H, 4.26; N, 11.77.

EXAMPLE 338[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(4-methyl-piperazin-1-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Heat a solution of(+)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(162 mg, 0.30 mmol) in 4-methylpiperazine (2.0 mL) to 100° C. After 18h., cool to RT and dilute with EtOAc (60 mL), then wash with IN HCl(2×10 mL), H₂O (10 mL), and saturated NaHCO₃ (10 mL). Dry, filter, andconcentrate the organic phase, and purify the crude material bydissolving in MeOH (2.0 mL) and applying to a Varian SCX column. Elutefirst with MeOH (30 mL) to remove unreacted(+)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanoneand then elute with 2N NH₃/MeOH to give the title compound (173 mg, 96%)as a white foam upon concentration of solvent. MS(ES) 601.4 (M+1)⁺; ¹HNMR (400 MHz, CDCl₃, mixture of amide rotamers) δ 7.84 (s, 0.5H), 7.83(s, 1H), 7.80 (s, 0.5H), 7.65 (s, 1H), 7.32 (m, 0.5H), 7.12 (m, 2H),7.96 (m, 1.5H), 6.25 (m, 0.5H), 5.62 (m, 0.5H), 5.50 (s, 1H), 5.32 (m,1H), 4.31 (m, 0.5H), 3.97 (m, 1H), 3.86 (m, 0.5H), 2.97 (m, 3H), 2.75(m, 1H), 2.41 (m, 5H), 2.27 (s, 1.5H), 2.25 (s, 1.5H), 1.94 (m, 3H).

EXAMPLE 3391-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-5,5-dimethyl-2-phenyl-pyrazolidin-3-one

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H[1,2,3]triazole-4-carboxylicacid (250 mg, 0.67 mmol) in CH₂Cl₂ (5 mL) and DMF (1 drop) and addoxalyl chloride (0.12 mL, 1.34 mmol). Stir 1.5 h at RT, then concentrateto dryness. Slurry in 1,2-dichloroethane and concentrate to dryness 2×.Dissolve the residue in pyridine (3 mL) in a sealed tube. Add acatalytic amount of DMAP (5 mg) and5,5-dimethyl-2-phenyl-3-pyrazolidinone (128 mg, 0.67 mmol). Heat for 2 hat 100° C., then concentrate to dryness. Dissolve in 20% iPrOH/CHCl₃.Wash with saturated aqueous NaHCO₃, and brine, dry over Na₂SO₄, filterand concentrate. Purify the residue via radial chromatography using aMeOH/CHCl₃ gradient to afford 147 mg (40%) of the title compound as awhite foam. ES(MS) 546.3 (M+1)⁺; R_(f)=0.58 (5% MeOH/CHCl₃).

Using a method similar to Example 339, with the appropriate startingmaterials, the following compounds may be prepared and isolated. Ex. #Product Data 340 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl- MS(ES)588.2(M+1)⁺; 1H-[1,2,3]triazole-4-carbonyl]-2-phenyl- pyrazolidin-3-one341 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES)589.1(M+1)⁺; yl-1H-[1,2,3]triazole-4-carbonyl]-5,5-dimethyl-2-R_(f)=0.44(10% MeOH/CHCl₃) phenyl-pyrazolidin-3-one 342[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 538.2(M+1)⁺;[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.55(5% MeOH/CHCl₃)pyrazolidin-1-yl]-methanone 343[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H- MS(ES) 580.4(M+1)⁺;[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- pyrazolidin-1-yl]-methanone344 (R,S)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4- MS(ES) 598.0(M+1)⁺;fluoro-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2- R_(f)=0.38(5% MeOH/CHCl₃)chloro-phenyl)-pyrazolidin-1-yl]-methanone 345(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4- MS(ES) 597.0(M+1)⁺;fluoro-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2- R_(f)=0.28(1:1EtOAc/hexanes) chloro-phenyl)-pyrazolidin-1-yl]-methanone 346[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 581.0(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.23(10%MeOH/CHCl₃) pyrazolidin-1-yl]-methanone 347[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 581.0(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.61(10%MeOH/CHCl₃) pyrazolidin-1-yl]-methanone 348[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrazin-2- MS(ES) 582.0(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.50(10%MeOH/CHCl₃) pyrazolidin-1-yl]-methanone 349[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 649.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-4- R_(f)=0.40(10% MeOH/CHCl₃)trifluoromethyl-phenyl)-pyrazolidin-1-yl]- methanone 350[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3- MS(ES) 649.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-4- R_(f)=0.60(10% MeOH/CHCl₃)trifluoromethyl-phenyl)-pyrazolidin-1-yl]- methanone 351[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3- MS(ES) 583.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2,4-difluoro- R_(f)=0.38(10% MeOH/CHCl₃)phenyl)-pyrazolidin-1-yl]-methanone 352[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 583.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2,4-difluoro- R_(f)=0.33(10% MeOH/CHCl₃)phenyl)-pyrazolidin-1-yl]-methanone 353[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3- MS(ES) 595.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.43(10%MeOH/CHCl₃) tetrahydro-pyridazin-1-yl]-methanone 354[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 595.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)- R_(f)=0.43(10%MeOH/CHCl₃) tetrahydro-pyridazin-1-yl]-methanone 355[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES) 565.9(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]-(8-chloro-3,4-dihydro- R_(f)=0.43(10%MeOH/CHCl₃) 2H-quinolin-1-yl)-methanone 356[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 522.9(M+1)⁺;[1,2,3]triazol-4-yl]-(8-chloro-3,4-dihydro-2H- R_(f)=0.60(1:1EtOAc/hexanes) quinolin-1-yl)-methanone 357cis-(R/S)-[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES) 622(M+1)⁺;pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-(2,4- R_(f)=0.48(1:1 EtOAc/hexanes)diphenyl-pyrrolidin-1-yl)-methanone

EXAMPLE 3581-[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-5,5-dimethyl-2-phenyl-pyrazolidin-3-one

Dissolve1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-5,5-dimethyl-2-phenyl-pyrazolidin-3-one(120 mg, 0.22 mmol) in morpholine (3 mL). Heat overnight at 100° C. in asealed tube, then concentrate to dryness. Dissolve the residue in 20%iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃, and brine, dry oversodium sulfate, filter, and concentrate to dryness. Purify the residuevia radial chromatography using a MeOH/CHCl₃ gradient to afford 16.4 mg(12.5%) of the title compound MS(ES) 597.4 (M+1)⁺; R_(f)=0.76 (10%MeOH/CHCl₃).

Using a method similar to the above example, with the appropriatestarting materials, the following compounds may be prepared andisolated. Ex. # Product Data 359 [1-(3,5-bis-trifluoromethyl-benzyl)-MS(ES) 589.3(M+1)⁺; 5-morpholin-4-yl-1H-[1,2,3]triazol- R_(f)=0.5(10%MeOH/CHCl₃) 4-yl]-[2-(2-chloro-phenyl)- pyrazolidin-1-yl]-methanone 360[1-(3,5-bis-trifluoromethyl-benzyl)- MS(IS) 522.9(M+); TLC5-morpholin-4-yl-1H-[1,2,3]triazol- R_(f)=0.5(1:1 EtOAc/hexanes)4-yl]-(8-chloro-3,4-dihydro- 2H-quinolin-1-yl)-methanone

EXAMPLE 361[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylicacid (100 mg,-0.23 mmol) in DMF (5 mL). Add2-(2-chlorophenyl)-pyrrolidine (46 mg, 0.25 mmol),hydroxy-azabenzotriazole (HOAt)(50 mg, 0.25 mmol), EDCI (35 mg, 0.25mmol), DMAP (5 mg) and TEA (0.1 mL, 0.69 mmol). Stir overnight at RT,then concentrate to dryness. Purify by radial chromatography using aMeOH/CHCl₃ gradient. Slurry the residue in ether/hexanes and concentrateto dryness to afford 87 mg (63%) of the title compound as a white foam.MS(ES) 597.0 (M+1)⁺; R_(f)=0.67 (5% MeOH/CHCl₃).

EXAMPLE 3621(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H[1,2,3]triazole-4-carboxylicacid (300 mg, 0.8 mmol) in CH₂Cl₂ (5 mL) and DMF (2 drops) and addoxalyl chloride (0.14 mL, 1.6 mmol). Stir for 1 h at RT, thenconcentrate the mixture to dryness. Slurry the residue in1,2-dichloroethane and concentrate to dryness twice. Dissolve theresidue in pyridine (3 mL) in a sealed tube. Add DMAP (5 mg, catalytic)and N-methyl-2-chloroaniline (120 mg, 0.8 mmol). Heat for 1 h at 80° C.,then concentrate to dryness. Dissolve in 20% iPrOH/CHCl₃. Wash withsaturated aqueous NaHCO₃, and brine, then dry over Na₂SO₄, filter, andconcentrate. Purify the residue via radial chromatography using an ethylacetate/hexanes gradient to afford 200 mg (50%) of the title compound asa colorless oil. MS(ES) 497.2 (M+1)⁺; R_(f)=0.625 (50% EtOAc/hexanes).

Using a similar method to that described above and the appropriatestarting materials, the following compounds may be prepared andisolated. Ex. # Product Data 3631-(3,5-bis-trifluoromethyl-benzyl)-5-(4-fluoro- MS(ES) 557.0(M+1)⁺;phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (2- R_(f)=0.52(5%MeOH/CHCl₃) chloro-phenyl)-methyl-amide 3641-(3,5-bis-trifluoromethyl-benzyl)-5-(pyridin-4- MS(ES) 540.0(M+1)⁺;yl)-1H-[1,2,3]triazole-4-carboxylic acid (2- R_(f)=0.58(5% MeOH/CHCl₃)chloro-phenyl)-methyl-amide 3651-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 540.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.50(10%MeOH/CHCl₃) phenyl)-methyl-amide 3661-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 530.9(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2,4-dichloro- R_(f)=0.75(5%MeOH/CHCl₃) phenyl)-methyl-amide 3671-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 554.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.43(10%MeOH/CHCl₃) methyl-phenyl)-methyl-amide 3681-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 573.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.70(5% MeOH/CHCl₃)dichloro-phenyl)-methyl-amide 3691-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 515.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.61(5% MeOH/CHCl₃)fluoro-phenyl)-methyl-amide 3701-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 558.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.44(10%MeOH/CHCl₃) fluoro-phenyl)-methyl-amide 3711-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(IS) 574.0(M+1)⁺;TLC 1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.50(10%MeOH/CHCl₃) dichlorophenyl)-methyl-amide 3721-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 558.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.38(10%MeOH/CHCl₃) fluoro-phenyl)-methyl-amide 3731-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 511.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro,4- R_(f)=0.57(5% MeOH/CHCl₃)methyl-phenyl)-methyl-amide 3741-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 554.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.48(1:1EtOAc/hexanes) methyl-phenyl)-methyl-amide 3751-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 574.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.36(10% MeOH/CHCl₃)dichloro-phenyl)-methyl-amide 3761-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 574.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.40(10% MeOH/CHCl₃)dichloro-phenyl)-methyl-amide 3771-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 542.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.50(10% MeOH/CHCl₃)difluoro-phenyl)-methyl-amide 3781-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 602.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.62(10% MeOH/CHCl₃)dichloro-phenyl)-isopropyl-amide 3791-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 602.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.40(10% MeOH/CHCl₃)dichloro-phenyl)-isopropyl-amide 3801-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 586.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.50(10%MeOH/CHCl₃) fluoro-phenyl)-isopropyl-amide 3811-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 586.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.57(10%MeOH/CHCl₃) fluoro-phenyl)-isopropyl-amide 3821-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 636.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.31(10%MeOH/CHCl₃) trifluoromethyl-phenyl)-isopropyl-amide 3831-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 636.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.68(10%MeOH/CHCl₃) trifluoromethyl-phenyl)-isopropyl-amide 3841-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 570.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.50(10% MeOH/CHCl₃)difluoro-phenyl)-isopropyl-amide 3851-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 570.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.50(10% MeOH/CHCl₃)difluoro-phenyl)-isopropyl-amide 3861-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 616.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.50(10% MeOH/CHCl₃)dichloro-benzyl)-isopropyl-amide 3871-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 616.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.58(10% MeOH/CHCl₃)dichloro-benzyl)-isopropyl-amide 3881-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 584.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.50(10% MeOH/CHCl₃)difluoro-benzyl)-isopropyl-amide 3891-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 584.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (3,4- R_(f)=0.37(10% MeOH/CHCl₃)difluoro-benzyl)-isopropyl-amide 3901-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 582.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.57(10%MeOH/CHCl₃) benzyl)-isopropyl-amide 3911-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 582.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.33(10%MeOH/CHCl₃) benzyl)-isopropyl-amide 3921-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 600.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.57(10%MeOH/CHCl₃) fluoro-benzyl)-isopropyl-amide 3931-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 557.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.67(1:1EtOAc/hexanes) fluoro-benzyl)-isopropyl-amide 3941-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 705.9(M+1)⁺1H-[1,2,3]triazole-4-carboxylic acid bis-(2,5- dichloro-phenyl)-amidetrifluoroacetate 395 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-MS(ES) 623.2(M+1)⁺; 1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-R_(f)=0.21(10% MeOH/CHCl₃) phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 3961-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 623.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.23(10%MeOH/CHCl₃) phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 3971-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 580.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.24(10% MeOH/CHCl₃)phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 3981-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 597.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.24(10%MeOH/CHCl₃) phenyl)-(2-dimethylamino-ethyl)-amide 3991-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 597.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.20(10%MeOH/CHCl₃) phenyl)-(2-dimethylamino-ethyl)-amide 4001-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 637.1(M+1)⁺1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.25(10%MeOH/CHCl₃) phenyl)-(2-piperidin-1-yl-ethyl)-amide 4011-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 637.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.27(10%MeOH/CHCl₃) phenyl)-(2-piperidin-1-yl-ethyl)-amide 4021-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 639.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.33(10%MeOH/CHCl₃) phenyl)-(2-morpholin-4-yl-ethyl)-amide 4031-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 639.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.25(10%MeOH/CHCl₃) phenyl)-(2-morpholin-4-yl-ethyl)-amide 4041-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 641.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.33(10%MeOH/CHCl₃) fluoro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 4051-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 641.2(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.34(10%MeOH/CHCl₃) fluoro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 4061-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 615.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.33(10%MeOH/CHCl₃) fluoro-phenyl)-(2-dimethylamino-ethyl)-amide 4071-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 615.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.20(10%MeOH/CHCl₃) fluoro-phenyl)-(2-dimethylamino-ethyl)-amide 4081-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 657.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.28(10%MeOH/CHCl₃) fluoro-phenyl)-(2-morpholin-4-yl-ethyl)-amide 4091-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 656.9(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.33(10%MeOH/CHCl₃) fluoro-phenyl)-(2-morpholin-4-yl-ethyl)-amide 4101-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 655.2(M+1);1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.33(10%MeOH/CHCl₃) fluoro-phenyl)-(2-piperidin-1-yl-ethyl)-amide 4111-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 655.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.30(10%MeOH/CHCl₃) fluoro-phenyl)-(2-piperidin-1-yl-ethyl)-amide 4121-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 631.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.33(10% MeOH/CHCl₃)dichloro-phenyl)-(2-dimethylamino-ethyl)-amide 4131-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 631.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.57(20% MeOH/CHCl₃)dichloro-phenyl)-(2-dimethylamino-ethyl)-amide 4141-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 657.0(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid (2,4- R_(f)=0.40(10% MeOH/CHCl₃)dichloro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 4151-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 572.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.50(10%MeOH/CHCl₃) fluoro-phenyl)-(2-dimethylamino-ethyl)-amide 4161-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 598.0(M+1)⁺;[1,2,3]triazole-4-carboxylic acid (2-chloro-4- R_(f)=0.50(10%MeOH/CHCl₃) fluoro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amide 4171-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 555.1(M+1)⁺[1,2,3]triazole-4-carboxylic acid (2-chloro- R_(f)=0.40(10% MeOH/CHCl₃)phenyl)-(2-dimethylamino-ethyl)-amide 4181-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 570.0(M+1)⁺.1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-(2-hydroxy-ethyl)-amide 419(R)-1-(3,5-bis-trifluoromethyl-benzyl)-5-(2H- MS(ES) 651.1(M+1)⁺;pyrazin-1-yl)-1H-[1,2,3]triazole-4-carboxylic acid R_(f)=0.23(10%MeOH/CHCl₃) [1-(2-chloro-phenyl)-ethyl]-(2-pyrrolidin-1-yl- ethyl)-amide420 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES)596.2(M+1)⁺ 1H-[1,2,3]triazole-4-carboxylic acid [1-(2-chloro-R_(f)=0.48(5% MeOH/CHCl₃) phenyl)-ethyl]-isopropyl-amide 4211-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 596.1(M+1)⁺1H-[1,2,3]triazole-4-carboxylic acid [1-(2-chloro- R_(f)=0.50(5%MeOH/CHCl₃) phenyl)-ethyl]-isopropyl-amide

EXAMPLE 4221-(3,5-bis-trifluoromethyl-benzyl)-5-(1-oxo-1-λ⁴-thiomorpholin-4-yl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide

Add m-chloroperbenzoic acid (40 mg, 0.176 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide (90 mg, 0.16 mmol) in CH₂Cl₂ (5 mL)at −78° C. After 30 min, quench with saturated K₂CO₃. Wash the organiclayer with saturated aqueous NaHCO₃, and brine, dry over sodium sulfate,filter, and concentrate. Purify by radial chromatography using aMeOH/CHCl₃ gradient to afford 75 mg (81%) of the title compound as awhite foam. MS(ES) 580.0 (M+1); R_(f)=0.34 (10% MeOH/CHCl₃).

EXAMPLE 423 1-(3,5-bis-trifluoromethyl-benzyl)-5-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-1H-[1,2,3]triazole4-carboxylic acid(2-chloro-phenyl)-methyl-amide

Add m-chloroperbenzoic acid (93 mg, 0.4 mmol) to a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide (90 mg, 0.16 mmol) in CH₂Cl₂ (5 mL)at 0° C. After 30 min, quench with saturated K₂CO₃. Wash the organiclayer with saturated aqueous NaHCO₃, and brine. Dry over sodium sulfate,filter, and concentrate. Purify by radial chromatography using aMeOH/CHCl₃ gradient to afford 53.1 mg (56%) of the title compound as awhite foam. MS(ES) 596.0 (M+1); R_(f)=0.54 (I 0% MeOH/CHCl₃).

EXAMPLE 4245-(4-acetyl-piperazin-1-yl)-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide (100 mg, 0.18 mmol) in CH₂Cl₂ (5mL). Add TEA (0.1 mL, 0.54 mmol), acetic anhydride (0.019 mL, 0.2 mmol)and DMAP (5 mg). Stir overnight at RT, then add water. Wash withsaturated aqueous NaHCO₃, and brine. Dry over sodium sulfate, filter,and concentrate. Purify by radial chromatography using a MeOH/CHCl3gradient afford 97 mg (92%) of the title compound as a tan foam. MS(ES)589.1 (M+1); R_(f)=0.58 (10% MeOH/CHCl₃).

EXAMPLE 4251-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide (200 mg, 0.4 mmol) in warmmorpholine (5 mL). Heat overnight at 100° C. in a sealed tube, thenconcentrate to dryness. Dissolve the residue in 20% iPrOH/CHCl₃. Washwith saturated aqueous NaHCO₃ and brine, dry over sodium sulfate,filter, and concentrate. Purify the residue via radial chromatographyusing an ethyl acetate/hexanes gradient to afford 155 mg (70%) of thetitle compound. MS(ES) 548.2 (M+1); R_(f)=0.41 (50% EtOAc/hexanes).

Using a similar method and the appropriate starting materials, thefollowing compounds may be prepared and isolated. Ex. # Product Data 4261-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl- MS(ES)564.4(M+1); 1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-R_(f)=0.63(1:1 methyl-amide EtOAc/hex) 4271-(3,5-bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H- MS(ES)547.1(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-R_(f)=0.38(20% methyl-amide MeOH/CHCl₃) 4281-(3,5-bis-trifluoromethyl-benzyl)-5-dimethylamino-1H- MS(ES)506.1(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-R_(f)=0.57(1:1 methyl-amide EtOAc/hexanes) 4291-(3,5-bis-trifluoromethyl-benzyl)-5-(4-methyl-piperazin- MS(ES)561.3(M+1); 1-yl)-1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-R_(f)=0.38(10% phenyl)-methyl-amide MeOH/CHCl₃) 4301-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)582.0(M+1); [1,2,3]triazole-4-carboxylic acid (2,4-dichloro-phenyl)-R_(f)=0.47(5% methyl-amide MeOH/CHCl₃) 4311-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)566.0(M+1)⁺; [1,2,3]triazole-4-carboxylic acid (2-chloro-4-flouro-R_(f)=0.61(5% phenyl)-methyl-amide MeOH/CHCl₃) 4321-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)562.0(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-4-methyl-R_(f)=0.54(5% phenyl)-methyl-amide MeOH/CHCl₃) 4331-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)608.1(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-4-fluoro-R_(f)=0.68(1:1 benzyl)-isopropyl-amide EtOAc/hexanes) 4341-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)631.2(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-(2-R_(f)=0.76(20% pyrrolidin-1-yl-ethyl)-amide MeOH/CHCl₃) 435(R,S)-(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES) 705.0(M+1);morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-[1-(2- R_(f)=0.50(1:1chloro-phenyl)-ethyl]-amino}-ethyl)-carbamic acid tert- EtOAc/hexanes)butyl ester 436{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl- MS(ES)691.1(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-R_(f)=0.40(1:1 ethyl}-carbamic acid tert-butyl ester EtOAc/hexanes) 437{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-methylamino- MS(ES)635.1(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-R_(f)=0.73(1:1 ethyl}-carbamic acid tert-butyl ester EtOAc/hexanes) 438{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-dimethylamino- MS(ES)649.0(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-R_(f)=0.65(1:1 ethyl}-carbamic acid tert-butyl ester EtOAc/hexanes) 439{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl- MS(ES)709.1(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-4-fluoro-R_(f)=0.51(1:1 benzyl)-amino]-ethyl}-carbamic acid tert-butyl esterEtOAc/hexanes) 4401-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(ES)639.0(M+1); [1,2,3]triazole-4-carboxylic acid (2-chloro-benzyl)-R_(f)=0.50(10% pyridin-4-ylmethyl-amide MeOH/CHCl₃) 4411-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H- MS(IS)606.0(M+); [1,2,3]triazole-4-carboxylic acid (2-chloro- TLCR_(f)=0.44(1:1 benzyl)-(2-methoxy-ethyl)-amide EtOAc/hexanes)

EXAMPLE 4421-(3,5-bis-trifluoromethyl-benzyl)-5-(4-methanesulfonyl-piperazin-1-yl)-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-methyl-amide (90 mg, 0.16 mmol) in CH₂Cl₂ (4 mL).Add TEA (0.1 mL, 0.48 mmol), methanesulfonyl chloride (0.014 mL, 0.176mmol) and DMAP (5 mg). Stir overnight at RT, then add water. Extractwith 20% iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃ and brine, dryover sodium sulfate, filter, and concentrate. Purify by radialchromatography using a MeOH/CHCl₃ gradient to afford 87 mg (87%) of thetitle compound as a tan foam. MS(ES) 625.0 (M+1)⁺; R_(f)=0.71 (10%MeOH/CHCl₃).

Using an analogous procedure and the appropriate starting materials, thefollowing compounds may be prepared and isolated. Stereoisomers can beseparated from the corresponding racemates via chiral chromatography.Ex. # Product Data 443 (R,S)-1-(3,5-bis-trifluoromethyl-benzyl)- MS(ES)674.9(M+1); 5-pyridin-4-yl-1H-[1,2,3]triazole- R_(f)=0.30(10%4-carboxylic acid [1-(2-chloro- MeOH/CHCl₃) phenyl)-ethyl]-(2-methanesulfonylamino-ethyl)-amide 4441-(3,5-bis-trifluoromethyl-benzyl)- MS(ES) 678.8(M+1).5-(2H-pyrazin-1-yl)-1H-[1,2,3]triazole- 4-carboxylic acid(2-chloro-4-fluoro- benzyl)-(2-methanesulfonylamino- ethyl)-amide 4451-(3,5-bis-trifluoromethyl-benzyl)- MS(ES) 688.9(M+1);5-morpholin-4-yl-1H-[1,2,3]triazole- R_(f)=0.50(10% 4-carboxylic acid(2-chloro-4-fluoro- MeOH/CHCl₃) benzyl)-(2-methanesulfonylamino-ethyl)-amide

EXAMPLE 446(R,S)-(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino-}-ethyl)-carbamicacid tert-butyl ester

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-pyrazin-2-yl-1H-[1,2,3]triazole-4-carboxylicacid (0.6 g, 1.4 mmol) in DMF (10 mL). Add(R,S)-{2-[1-(2-chloro-phenyl)-ethylamino]-ethyl}-carbamic acidtert-butyl ester (628 mg, 2.1 mmol), HOAt (208 mg, 1.5 mmol) EDCI (300mg, 1.5 mmol), DMAP (5 mg) and TEA (0.22 mL, 1.5 mmol) in 10 mL of DMFand stir at RT. After 16 h, concentrate the mixture and dissolve theresidue in 20% iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃ andbrine, dry over sodium sulfate, filter, and concentrate. Purify theresidue by column chromatography using a methanol/chloroform gradient toafford 718 mg (74%) of the title compound as a tan oil. MS(ES) 697.2(M+1)⁺; R_(f)=0.40 (10% MeOH/CHCl₃).

Using a similar method and the appropriate starting materials, thefollowing compounds may be prepared and isolated. Ex. # Product Data 447(R,S)-(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro- MS(ES)654.0(M+1); 1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-R_(f)=0.60(1:1 ethyl]-amino}-ethyl)-carbamic acid tert-butyl esterEtOAc/hexanes) 448{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES)683.06(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-Rf=0.29(10% amino]-ethyl}-carbamic acid tert-butyl ester MeOH/CHCl₃) 449{2[[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 640.0(M+1);[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]- Rf=0.60(1:1ethyl}-carbamic acid tert-butyl ester EtOAc/hexanes) 450{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES)701.1(M+1); 1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-4-fluoro-Rf=0.37(10% benzyl)-amino]-ethyl}-carbamic acid tert-butyl esterMeOH/CHCl₃) 451 {2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-MS(ES) 658.0(M+1);[1,2,3]triazole-4-carbonyl]-(2-chloro-4-fluoro-benzyl)- Rf=0.61(1:1amino]-ethyl}-carbamic acid tert-butyl ester EtOAc/hexanes) 4521-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H- MS(ES) 630.9(M+1);[1,2,3]triazole-4-carboxylic acid (2-chloro-benzyl)- Rf=0.75(20%pyridin-4-ylmethyl-amide MeOH/CHCl₃) 4531-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H- MS(ES) 587.9(M+1);[1,2,3]triazole-4-carboxylic acid (2-chloro-benzyl)- Rf=0.62(10%pyridin-4-ylmethyl-amide MeOH/CHCl₃) 4541-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H- MS(ES) 597.9(M+1);[1,2,3]triazole-4-carboxylic acid (2-chloro-benzyl)-(2- Rf=0.60(10%methoxy-ethyl)-amide MeOH/CHCl₃)

EXAMPLE 455(R,S)-1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridyl-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide dihydrochloride

Dissolve(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamicacid tert-butyl ester (1.07 g, 1.53 mmol) in HCl-saturated acetic acid(20 mL). Stir for 3 h at RT, then concentrate to dryness. Dissolve inCH₃CN and concentrate to dryness. Dry under vacuum to afford 1.02 g(100%) of the title compound as a white foam. MS(ES) 598.1 (M+1)⁺; Anal.Calc'd for C₂₇H₂₃ClF₆N₆O22HCl: C, 47.89;H, 3.75; N, 12.41. Found: C,47.61;H, 3.81; N, 12.20.

Using a method analogous to the above method, with the appropriatestarting materials, the following compounds may be prepared andisolated. Stereoisomers can be separated from the correspondingracemates via chiral chromatography. Ex. # Product Data 456(R,S)-1-(3,5-bis-trifluoromethyl-benzyl)-5- MS(ES) 605.2(M+1); Anal.morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylic Calc'd for acid(2-amino-ethyl)-[1-(2-chloro-phenyl)- C₂₆H₂₇ClF₆N₆O₂.2.5HCl: C, 44.86;ethyl]-amide dihydrochloride H, 4.27; N, 12.07. Found: C, 44.82; H,4.51; N, 11.60. 457 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-MS(ES) 583.1(M+1); Anal Calcd yl-1H-[1,2,3]triazole-4-carboxylic acid(2- for C₂₆H₂₁ClF₆N₆0.2HCl: C, amino-ethyl)-(2-chloro-benzyl)-amide47.61; H, 3.53; N, 12.81. Found: dihydrochloride C, 47.25; H, 3.42; N,12.44. 458 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4- MS(ES)601.1(M+1); Anal Calcd yl-1H-[1,2,3]triazole-4-carboxylic acid (2- forC₂₆H₂₀ClF₇N₆O.2HCl: C, amino-ethyl)-(2-chloro-4-fluoro-benzyl)-amide46.34; H, 3.29; N, 12.47. Found: dihydrochloride C, 46.40; H, 3.65; N,11.80. 459 1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin- MS(ES)609.0(M+1); Anal. 4-yl-1H-[1,2,3]triazole-4-carboxylic acid (2- Calc'dfor C₂₅H₂₄ClF₇N₆O₂.HCl: amino-ethyl)-(2-chloro-4-fluoro-benzyl)-amide C,46.52; H, 3.90; N, 13.02. hydrochloride Found: C, 46.50; H, 4.11; N,12.62 460 1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin- MS(IS)591.1(M+1); Anal. 4-yl-1H-[1,2,3]triazole-4-carboxylic acid (2- Calc'dfor C₂₅H₂₅ClF₆N₆O₂.HCl: amino-ethyl)-(2-chloro-benzyl-amide C, 47.86; H,4.18; N, 13.39. hydrochloride Found: C, 47.71; H, 4.27; 13.06. 4611-(3,5-bis-trifluoromethyl-benzyl)-5- MS(IS) 534.9(M+1);methylamino-1H-[1,2,3]triazole-4-carboxylic acid(2-amino-ethyl)-(2-chloro-benzyl)-amide hydrochloride 4621-(3,5-bis-trifluoromethyl-benzyl)-5- MS(IS) 548.9(M+1); Anal.dimethylamino-1H-[1,2,3]triazole-4-carboxylic Calc'd forC₂₃H₂₃ClF₆N₆O.1.1HCl: acid (2-amino-ethyl)-(2-chloro-benzyl)-amide C,46.90; H, 4.12; N, 14.27. hydrochloride Found: C, 46.76; H, 4.00; N,13.78.

EXAMPLE 463N-[1-(3,5-bis-trifluoromethyl-benzyl)-5-(2H-pyrazin-1-yl)-1H-[1,2,3]triazole-4-carbonyl]-2-chloro-N-methyl-benzenesulfonamide

Dissolve1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole4-carboxylicacid (300 mg.; 1.0 eq.) in CH₂Cl₂ (5 mL). Add2-chloro-N-methylbenzenesulfonamide (178 mg., 1.0 eq.), DMAP (90 mg.;1.0 eq.) and EDCI (280 mg, 1.0 eq.). Stir overnight at RT, then dilutewith CH₂Cl₂ (10 mL) and wash with saturated aqueous NaHCO₃, and brine.Dry the organic layer over sodium sulfate, filter, and concentrate todryness. Purify by chromatography. MS(ES) 603.9 (M+1)⁺; R_(f)=0.57 (10%MeOH/CHCl₃).

EXAMPLE 464N-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl)-2-chloro-N-methyl-benzamide

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylicacid (600 mg., 1.0 eq.) in CH₂Cl₂ (10 mL) and DMF (I drop). Add oxalylchloride (0.3 mL, 2.0 eq.) and stir for 2 hours at RT. Concentrate themixture and slurry the residue in 1,2-dichloroethane and concentrate todryness again. Dissolve in DMF and cool to 0° C. Separately, add2-chloro-N-methyl-benzamide (250 mg., 1.0 eq.) to a slurry of NaH (70mg, 1.2 eq.) in DMF at 0° C. Add the NaH mixture to the acid chloridesolution. Stir 10 minutes, then remove the ice bath and stir overnightat RT. Concentrate the mixture in vacuo and dissolve the residue in 20%iPrOH/CHCl₃. Wash with saturated aqueous NaHCO₃, and brine, dry overNa₂SO₄, filter, and concentrate. Purify the residue by reverse phasechromatography. MS(ES) 567.9 (M+1); Rf=0.66 (10% MeOH/CHCl₃).

EXAMPLE 465[1-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl]-methanone

Dissolve [1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl]-methanone (60 mg,0.11 mmol) in morpholine (1.2 mL) and heat solution at 100° C. in asealed tube for 12 h. Concentrate the mixture and purify the residue bychromatography using a gradient of 10:1 to 1:5Hex/EtOAc to afford thetitle compound (46 mg, 70%). MS(ES) 602.5 (M+1).

EXAMPLE 466[1-(3,5-Bis-trifluoromethyl-benzyl)-5-dimethylamino-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl]-methanone

Add dimethyamine (1 ml, 2.0 M in THF) to[1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl]-methanone(60 mg, 0.11 mmol) and heat to 100° C. in a sealed tube for 12 h. Coolreaction to RT, add more dimethyamine (1 ml, 2.0 M in THF), and againheat to 100° C. After 12 h, add a third aliquot of dimethylamine (1 ml,2.0 M in THF) and heat to 100° C. for another 12 h. Then 2 0 concentratethe mixture and purify the residue by chromatography using a gradient of10:1 to 1:5Hex/EtOAc to afford title compound (23.6 mg, 38%). MS(ES)560.1 (M+1); Rf=0.22 (2:1Hex/EtOAc).

EXAMPLE 467[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[3-(2-chloro-phenyl)-piperidin-1-yl]-methanone

To a solution of1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (50 mg, 0.12 mmol) and HOBt (85 mg, 0.36 mmol) in CH₂Cl₂ (1 mL) add3-(2-chloro-phenyl)-piperidine (33.4 mg, 0.17 mmol) and stir at RT. Tothis solution add TEA (83.5 μL, 0.60 mmol) and EDCI (69 mg, 0.36 mmol).Stir at RT for 24 h, then dilute the solution with CH₂Cl₂ (1 mL), andwash with 1N HCl (2×1.5 mL). Wash the organic layer with 1N NaOH (2×1.5mL), saturated NaHCO₃ (1 mL) and brine (1 mL). Dry, filter andconcentrate. Purify the residue by chromatography using a gradient of10:1 to 1:5Hex/EtOAc to afford title compound (49.7 mg, 70%). MS (ES)594.1 (M+1)⁺; Rf=0.41 (1:5Hex/EtOAc).

EXAMPLE 468[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[cis-2-(2-chloro-phenyl)-3-hydroxy-pyrrolidin-1-yl]-methanone

Treat acetic acid cis-2-(2-chloro-phenyl)-pyrrolidin-3-yl ester (615 mg,2.57 mmol) and1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid hydrochloride (1.16 g, 2.57 mmol) in 20 mL of DMF with EDCI (591mg, 3.08 mmol), HOBt (417 mg, 3.08 mmol) and a catalytic amount of DMAP.Stir at RT for 20 h, then dilute with saturated aqueous NaHCO₃ andextract with EtOAc (100 mL).

Wash the organic layer with brine, then dry over MgSO₄, filter, andconcentrate. Purify by chromatography using 1% MeOH in dichloromethaneto provide the acetate intermediate (acetic acid1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-2-(2-chloro-phenyl)-pyrrolidin-3-ylester. Dilute this material with a mix of dioxane and water (20 mL:5 mL)and add LiOH.H₂O (502 mg, 12 mmol). Stir at RT for 72 h, thenconcentrate in vacuo. Partition the residue between EtOAc and H₂O (75 mLeach). Wash the organic layer with saturated aqueous NaHCO₃ and brine(75 mL each) and dry over Na₂SO₄, then filter and concentrate. Purify bychromatography using 1% MeOH in dichloromethane doped with a solution of25% NH₄OH to give the title compound as an off-white solid (830 mg, 54%over 2 steps). ¹H NMR (CDCl₃, 400 MHz): δ 2.04-2.28 (m, 2H), 3.88-4.03(m, 1H), 4.21-4.26 (m, 0.5H), 4.45-4.52 (m, 0.5H), 4.75-4.80 (m, 1H),5.34 (AB q, J=16 Hz, Δv=48 Hz, 1H), 5.54 (AB q, J=16 Hz, Δv=23 Hz, 1H),5.62 (d, J=5.2 Hz, 0.5H), 6.41 (d, J=5.6 Hz, 0.5H), 6.95-7.04 (m, 2.5H),7.17-7.31 (m, 3H), 7.35-7.37 (m, 1.5H), 7.51 (s, 1H), 7.82 (s, 0.5H),7.85 (s, 0.5H), 8.7 (s, 2H), MS(ES) 596.17 (M+1).

EXAMPLE 469[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[trans-2-(2-chloro-phenyl)-3-hydroxy-pyrrolidin-1-yl]-methanone

Treat[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[cis-2-(2-chloro-phenyl)-3-hydroxy-pyrrolidin-1-yl)-methanone(125 mg, 0.21 mmol) with 4-nitrobenzoic acid (141 mg, 0.84 mmol), DIAD(165 uL, 0.84 mmol) and triphenyl phosphine (221 mg, 0.84 mmol) in 3.1mL of THF at 0° C. for 18 h. Dilute the mixture with EtOAc and wash twotimes with saturated aqueous NaHCO₃. Dry the organic layer over Na₂SO₄,filter and concentrate. Purify by chromatography using 2% MeOH indichloromethane to provide the nitrobenzoate ester intermediate(4-nitro-benzoic acid1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole4-carbonyl]-2-(2-chloro-phenyl)-pyrrolidin-3-ylester). Dissolve this material in dioxane/water and add LiOH.H₂O (50 mg,0.42 mmol). Stir at RT for 8 b, then concentrate and purify the residueby column chromatography using 30% EtOAc/hexanes to provide the titlecompound as an off-white foam (46 mg, 37% over 2 steps). ¹H NMR (CDCl₃,400 MHz): δ 1.94-2.24 (m, 2H), 4.03 (dd, J=9.6, 5.6 Hz, 1H), 4.28 (ddd,J=11.6, 8, 8 Hz, 0.5H), 4.38 (s, 0.5H), 4.65 (s, 0.5H), 4.83 (t, J=9.2Hz, 0.5H), 5.39 (s, 1H), 5.50-5.59 (m, 1.5H), 6.25 (s, 0.5H), 6.96 (d,J=7.6 Hz, 0.5H), 7.03 (d, J=5.6 Hz, 1H), 7.08-7.20 (m, 3.5H), 7.33-7.36(m, 2H), 7.51 (s, 1H), 7.81 (s, 0.5H), 7.85 (s, 0.5H), 8.7 (s, 2H);MS(ES) 596.20 (M+1).

EXAMPLE 470[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[cis-2-(2-chloro-phenyl)-4-hydroxy-pyrrolidin-1-yl]-methanone

Dissolvecis-4-(tert-butyl-dimethyl-silanyloxy)-2-(2-chloro-phenyl)-pyrrolidine(150 mg, 0.48 mmol) and1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid hydrochloride (240 mg, 0.53 mmol) in 10 mL of dichloromethane andadd EDCI (110 mg, 0.58 mmol), HOBt (78 mg, 0.58 mmol) and triethylamine(80 uL, 0.58 mmol). Stir the mixture at RT for 20 h, then dilute withsaturated NaHCO₃ and extract with EtOAc(20 mL). Wash the organic layerwith brine, dry, filter and concentrate. Dissolve the crude product,[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-2-(2-chloro-phenyl)-pyrrolidin-1-yl)-methanone(75 mg, 0.106 mmol), in THF (3 mL) and TBAF (120 uL of a 1M soln. inTHF, 0.12 mmol). Stir the mixture for 1 h at RT, then dilute with EtOAcand wash with brine. Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify the residue by chromatography using 2% MeOH and 0.5%conc. NH₄OH in dichloromethane to give the title compound as a off-whitefoam (36 mg, 13% over 2 steps). ¹H NMR (CDCl₃, 400 MHz) δ 1.98 (ddd,J=12.8, 4.4, 4.4 Hz, 1H), 2.07-2.12 (m, 1H), 2.62 (ddd, J=14, 8.8, 5.6Hz, 0.5H), 2.74 (ddd, J=14.4, 9.2, 6 Hz, 0.5H), 3.84 (d, J=12.4 Hz,0.5H), 4.04 (dd, J=13.6, 5.6 Hz, 0.5H), 4.35 (dd, J=12.4, 5.2 Hz, 0.5H),4.49 (d, J=12 Hz, 0.5H), 4.53-4.56 (m, 1H), 5.33 (s, 1H), 5.50-5.56 (m,1.5H), 6.33 (dd, J=9.2, 3.6 Hz, 0.5H), 6.70-6.92 (m, 1H), 7.04-7.18 (m,2H), 7.22-7.37 (m, 3H), 7.41 (s, 1H), 7.50 (d, J=7.6 Hz, 0.5H), 7.61 (d,J=8.5 Hz, 0.5H), 7.73 (s, 0.5H), 7.76 (s, 0.5H), 8.17 (s, 0.5H), 8.51(s, 0.5H), 8.64 (s, 1H); R_(f)=0.46 (5% MeOH/CH₂Cl₂).

EXAMPLE 471[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-4,4-difluoro-pyrrolidin-1-yl)-methanone

Dissolve[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[cis-2-(2-chloro-phenyl)-4-hydroxy-pyrrolidin-1-yl]-methanone(36 mg, 0.06 mmol) in dichloromethane (2.5 ml), chill to 0° C., and addDess-Martin periodinane (31 mg, 0.073 mmol). Stir 12 h, allowing to warmto RT. Dilute with ethyl acetate (20 ml), wash with 5N aqueous sodiumhydroxide (2×15 ml) and brine (20 ml). Dry organic phase over sodiumsulfate, filter and concentrate. Chromatograph residue on silica gel(0.5% ammonium hydroxide/2% methanol/dichloromethane)[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-4-oxo-pyrrolidin-1-yl]-methanone(30 mg, 80%). Dissolve this material in dichloromethane (2 ml) and add(diethylamino)sulfur trifluoride (50 μl, 0.38 mmol). Stir at RT for 12h, then slowly add saturated aqueous sodium bicarbonate solution (5 ml).Extract with ethyl acetate (2×15 ml) and wash the organic phase withbrine (10 ml). Dry over sodium sulfate, filter, and concentrate. Purifythe residue by chromatography on silica gel (0.5% ammonium hydroxide/] %methanol/dichloromethane) to give the title compound as a light yellowsolid (18 mg, 58%). MS(ES) 616.1 (M+1); ¹H NMR (CDCl₃, 400 MHz): δ2.25-2.50 (m, 1H), 2.85-3.09 (m, 1H), 4.02-4.24 (m, 1H), 4.59 (dd,J=22.4, 12.4 Hz, 0.5H), 4.73 (dd, J=30, 14 Hz, 0.5H), 5.34 (s, 1H), 5.55(AB q, J=15.6 Hz, Δv=16 Hz, 1H), 5.69 (dd, J=9.2, 6 Hz, 0.5H), 6.56 (dd,J=9.2, 4.4 Hz, 0.5H), 6.93-7.06 (m, 1.5H), 7.09-7.17 (m, 1.5H),7.20-7.35 (m, 2.5H), 7.40-7.50 (m, 2H), 7.55 (dd, J=8 Hz, 1H), 7.30 (s,0.5H), 7.76 (s, 1H), 8.17 (s, 0.5H), 8.51 (s, 0.5H), 8.65 (s, 1H).

EXAMPLE 472[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrol-1-yl]-methanone

Suspend1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3)triazole-4-carboxylicacid (1 g, 2.41 mmol) in dichloromethane (10 ml), add oxalyl chloride(2M in dichloromethane, 2.4 ml, 4.82 mmol) and two drops ofdimethylformamide. Stir for 2 h, then remove solvent. Suspend theresidue in dichloromethane (8 mL) and add the suspension to a solutionof pyridine (1 ml, 12.4 mmol),5-(2-chloro-phenyl)-3,4-dihydro-2H-pyrrole (865 mg, 4.82 mmol), and4-dimethylaminopyridine (20 mg). Stir at RT. After 18 h, dilute withethyl acetate (60 ml) and wash with 2N HCl (50 ml), brine (50 ml), andsaturated aqueous NaHCO₃ (50 ml). Dry over sodium sulfate, filter, andconcentrate. Dissolve residue in 1,4-dioxane and add2,3-dichloro-5,6-dicyano-1,4-benzoquinone (600 mg, 2.64 mmol). Stir atRT for 18 h. Then remove the solvent and dissolve residue in ethylacetate (60 ml). Wash with 1N NaOH (50 ml), and brine (50 ml). Dry oversodium sulfate, filter, and concentrate. Purify the residue bychromatography on silica gel (15% ethyl acetate/hexane) to give thetitle compound as a light purple solid (150 mg, 11% over 2 steps): ¹HNMR (CDCl₃, 400 MHz): δ 5.50 (s, 2H), 6.32 (dd, J=3.2, 1.6 Hz, 1H), 6.35(t, J=3.6 Hz, 1H), 7.08-7.23 (m, 5H), 7.35 (dd, J=7.6, 1.6 Hz, 1H),7.40-7.51 (m, 5H), 7.67 (dd, J=3.6, 1.6 Hz, 1H), 7.80 (s, 1H); MS(ES)575.0 (M+1)⁺.

EXAMPLE 473[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Treat a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylicacid (0.20 g, 0.49 mmol) in CH₂Cl₂ (3.0 mL) with EDCI (0.20 g, 1.0mmol), DMAP (0.13 g, 1.1 mmol) and (±)-2-(2-chloro-phenyl)-pyrrolidine(0.26 g, 0.95 mmol). Stir at RT overnight, then dilute with additionalCH₂Cl₂ (20 mL) and wash with saturated NH₄Cl (10 mL), H₂O (10 mL), andsaturated NaHCO₃ (10 mL). Dry, filter, and concentrate the organicsolution, then purify by flash chromatography using a linear gradient of70% EtOAc/hexanes to 100% EtOAc. Purify again by flash chromatographyusing a linear gradient of 100% CH₂Cl₂ to 10% MeOH/CH₂Cl₂ to give thetitle compound (0.17 g, 65%). MS (ES+) 580.3 (M+1)⁺; ¹H NMR (400 MHz,CDC13) δ 8.69 (m, 1H), 8.55 (m, 0.5H), 8.20 (m, 0.5H), 7.82 (s, 0.5H),7.79 (s, 0.5H), 7.67 (m, 0.5H), 7.54 (m, 0.5H), 7.47 (m, 1H), 7.29-7.40(m, 3H), 7.10-7.24 (m, 1.5H), 7.06 (m, 0.5H), 7.01 (m, 0.5H), 6.90 (m,0.5H), 6.30 (m, 0.5H), 5.60 (m, 1.5H), 5.41 (m, 1H), 4.55 (m, 0.5H),4.11 (m, 0.5H), 3.90 (m, 0.5H), 3.81 (m, 0.5H), 2.50 (m, 0.5H), 2.41 (m,0.5H), 1.84-2.02 (m, 3.5H).

EXAMPLE 474[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Using a method similar to that for[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone,the title compound may be prepared. The racemate may be separated viachiral chromatography (Chiralcell OD 4.6mm×250mm, 20%isopropanol/heptane, 1 mL/min) to give(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone. MS (ES+)580.3 (M+1), MS (ES−) 578.5 (M−1). 1HNMR (400 MHz, CDCl3) δ 8.69 (s,2H), 7.85 (s, 0.5H), 7.81 (s, 0.5H), 7.53 (s, 1H), 7.39 (s, 1H),7.22-7.32 (m, 2H), 7.11-7.17 (m, 1.5H), 7.03 (m, 1.5H), 6.99 (m, 0.5H),6.89 (m, 0.5H), 6.26 (m, 0.5H), 5.56-5.60 (m, 1.5H), 5.38 (m, 1H), 4.53(m, 0.5H), 4.11 (m, 0.5H), 3.90 (m, 0.5H), 3.83 (m, 0.5H), 2.50 (m,0.5H), 2.41 (m, 0.5H), 1.85-2.02 (m, 3.5H).

EXAMPLE 475[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxy-pyridin-4-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)pyrrolidin-1-yl]-methanone

Treat a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(81 mg, 0.14 mmol) in CH₂Cl₂ (1.5 mL) with mCPBA (52 mg, 0.30 mmol) andstir solution at RT overnight. Dilute solution with CH₂Cl₂ (20 mL) andwash with saturated aqueous NaHCO₃ (20 mL). Dry, filter, and concentratethe organic layer, and purify the crude material by flash chromatographyby first eluting with 100% EtAc to remove unreacted starting materialand then eluting with 10% MeOH/CH₂Cl₂ to give the title compound as aclear glass. Dissolve the solid in minimal amount of ether andprecipitate with hexanes to give a white amorphous solid (66mg, 79%).MS(ES) 596.1 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, 1:1 mixture of amiderotamers) δ 8.16 (m, 2H), 7.85 (m, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.32(m, 0.5H), 7.20 (m, 1H), 7.17 (m, 2H), 7.00 (m, 1H), 6.96 (m, 1H), 6.87(m, 0.5H), 6.22 (m, 0.5H), 5.57 (m, 0.5H), 5.56 (s, 1H), 5.37 (m, 1H),4.52 (m, 0.5H), 4.08 (m, 0.5H), 3.87 (m, 1H), 2.44 (m, 1H), 1.98 (m,2H), 1.89 (m, 1H).

EXAMPLE 476[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxy-pyridin-3-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Treat a solution of[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-3-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(77 mg, 0.13 mmol) in CH₂Cl₂ (1.5 mL) with mCPBA (90 mg, 0.52 mmol) andstir solution at RT for 60 h. Dilute the solution with CH₂Cl₂ (25 mL)and wash with saturated aqueous NaHCO₃ (15 mL). Dry, filter, andconcentrate the organic layer. Dissolve the crude glassy material in aminimal amount of ether and precipitate with hexanes to give the titlecompound as a white amorphous solid. MS(ES) 596.1 (M+1)⁺; ¹H NMR (400MHz, CDCl₃, 1:1 mixture of amide rotamers) δ 8.20 (m, 1H), 8.10 (s,0.5H), 7.84 (s, 0.5H), 7.80 (m, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.25(m, 2H), 7.14 (m, 1H), 7.06 (m, 1H), 7.03 (m, 1H), 6.91 (m, 1H), 6.27(m, 0.5H), 5.58 (m, 1H), 5.54 (m, 0.5H), 5.39 (s, 1H), 4.53 (m, 0.5H),4.11 (m, 0.5H), 3.89 (m, 0.5H), 3.80 (m, 0.5H), 2.44 (m, 1H), 1.98 (m,1H), 1.99 (m, 2H).

EXAMPLE 477(±)-(1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (1.8 g, 4.8 mmol), (±)-2-(2-chloro-phenyl)-pyrrolidine (1.1 g, 5.89mmol) and DMAP (1.4 g, 11.4 mmol) in CH₂Cl₂ (45 mL) and add EDCI (1.4 g,7.1 mmol). Stir the solution at RT for 24 h, then dilute with additionalCH₂Cl₂ (50 mL) and wash with saturated NH₄Cl (50 mL) and saturatedNaHCO₃ (50 mL). Dry, filter, and concentrate the organic phase. Purifycrude material by flash chromatography using a linear gradient of 10% to50% EtOAc/hexanes to give the title compound (2.1 g, 83%) as a whitefoam upon concentration of solvent. MS(ES) 537.0 (M+1)⁺; ¹H NMR (400MHz, CDCl₃, mixture of amide rotamers) δ 7.88 (s, 0.5H), 7.84 (s, 0.5H),7.80 (s, 1H), 7.64 (s, 1H), 7.33 (m, 0.5H), 7.16 (m, 2H), 7.00 (m,1.5H), 6.23 (m, 0.5H), 5.64 (m, 1.5H), 5.46 (s, 1H), 4.44 (m, 0.5H),4.12 (m, 0.5H), 4.01 (m, 0.5H), 3.87 (m, 0.5H), 2.43 (m, 1H), 2.00 (m,2H), 1.88 (m, 1H).

EXAMPLE 478 (S)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Heat a solution of(S)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(63mg, 0.12mmol) in morpholine (1.0 mL) to 50-60° C. After 48 h, cool toRT and dilute with EtOAc (30 mL). Wash with 1N HCl (10 mL), H₂O (10 mL),and saturated NaHCO₃ (10 mL). Dry, filter, and concentrate the organicphase. Purify the crude material by flash chromatography using a lineargradient of 20% to 60% EtOAc/hexanes to give(−)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(37 mg, 54%) as a white foam. MS(ES) 588.2 (M+])⁺; ¹H NMR (400 MHz,CDCl₃, mixture of amide rotamers) δ 7.85 (s, 0.5H), 7.83 (s, 1H), 7.81(s, 0.5H), 7.65 (s, 1H), 7.34 (m, 0.5H), 7.16 (m, 2H), 7.96 (m, 1.5H),6.31 (m, 0.5H), 5.64 (m, 0.5H), 5.54 (s, 1H), 5.36 (d, 1H, J=3.4 Hz),4.37 (m, 0.5H), 3.99 (m, 1H), 3.90 (m, 0.5H), 3.59-3.73 (m, 4H),2.87-2.98 (m, 3H), 2.74 (m, 1H), 2.46 (m, 1H), 1.96 (m, 3H).

Using a similar method to that above, with the appropriate startingmaterials, the following compound may be prepared. Ex. # Product Data479 (S)-[1-(3,5-Bis- MS(ES) 601.4(M+1)⁺; ¹H NMR(400MHz, CDCl₃,trifluoromethyl-benzyl)-5- mixture of amide rotamers) δ 7.84(s, 0.5H),7.83(s, (4-methyl-piperazin-1-yl)- 1H), 7.80(s, 0.5H), 7.65(s, 1H),7.32(m, 0.5H), 1H-[1,2,3]triazol-4-yl]-[2- 7.12(m, 2H), 7.96(m, 1.5H),6.25(m, 0.5H), 5.62(m, (2-chloro-phenyl)- 0.5H), 5.50(s, 1H), 5.32(m,1H), 4.31(m, 0.5H), pyrrolidin-1-yl]-methanone 3.97(m, 1H), 3.86(m,0.5H), 2.97(m, 3H), 2.75(m, 1H), 2.41(m, 5H), 2.27(s, 1.5H), 2.25(s,1.5H), 1.94(m, 3H).

EXAMPLE 480(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazol4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Add(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-[(2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.25 g, 0.47 mmol) to piperazine (0.10 g, 1.16 mmol) and heat to 100°C. in a sealed tube for 16 h. Dilute the reaction mixture with ethylacetate, wash with water and brine, then dry, and concentrate. Purifythe residue by flash chromatography using a linear gradient of 5 to 9%MeOH in dichloromethane to give the title compound (0.25 g, 92%) aswhite solid. MS(ES) 587.3 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, mixture ofamide rotamers) δ 7.86 (s, 1.5H), 7.82 (s, 0.5H), 7.68 (s, 1H), 7.36 (s,0.5H), 7.14-7.19 (m, 2H), 6.97 (m, 1.5H), 6.32 (m, 0.5H), 5.65 (m,0.5H), 5.54 (m, 1H), 5.36 (m, 1H), 4.36 (m, 0.5H), 3.96-4.08 (m, 1H),3.90 (m, 0.5H), 2.85-2.91 (m, 8H), 2.70 (m, 1H), 2.46 (m, 1H), 1.91-2.03(m, 3H).

Using an analogous procedureto(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanonedescribed above, with the appropriate starting materials, the followingcompounds may be prepared. Ex. # Product Data 481 (R)-[1-(3,5-Bis-MS(ES) 604.2(M+1)⁺; ¹H NMR(400MHz, CDCl₃, trifluoromethyl-benzyl)-5-mixture of amide rotamers) δ 7.82(m, 2H), 7.64(s, thiomorpholin-4-yl-1H-1H), 7.34(m, 0.5H), 7.12-7.20(m, 2.5H), 6.98(m,[1,2,3]triazol-4-yl]-[2-(2- 1H), 6.35(m, 0.5H), 5.65(m, 0.5H), 5.52(s,1H), chloro-phenyl)-pyrrolidin-1- 5.33(s, 1H), 4.34(m, 0.5H),3.90-4.11(m, 1.5H), yl]-methanone 2.66(s, 3H), 2.57(s, 3H), 2.45(m, 1H),1.87-2.02(m, 3H). 482 (R)-[1-(3,5-Bis- MS(ES) 546.3(M+1)⁺. ¹HNMR(400MHz, CDCl₃, trifluoromethyl-benzyl)-5- mixture of amide rotamers)δ 7.88(s, 0.5H), 7.83(s, dimethylamino-1H- 1.5H), 7.64(s, 1H), 7.37(s,0.5H), 7.17(m, 2H), [1,2,3]triazol-4-yl]-[2-(2- 6.70(m, 1.5H), 6.36(m,0.5H), 5.67(m, 0.5H), chloro-phenyl)-pyrrolidin-1- 5.52(m, 1H), 5.35(m,1H), 4.40(m, 0.5H), 4.02(m, 1H), yl]-methanone 3.91(m, 0.5H),3.12-3.22(m, 3H), 3.00(m, 0.5H), 2.58-2.70(m, 3H), 2.48(m, 0.5H),1.96(m, 3H). 483 (R)-[1-(3,5-Bis- MS(ES) 602.2(M+1)⁺. ¹H NMR(400MHz,CDCl₃, trifluoromethyl-benzyl)-5-(4- mixture of amide rotamers) δ7.87(s, 0.5H), 7.85(s, hydroxy-piperidin-1-yl)-1H- 1H), 7.82(s, 0.5H),7.67(s, 1H), 7.35(m, 0.5H), [1,2,3]triazol-4-yl]-[2-(2- 7.14-7.19(m,2H), 6.96(m, 1.5H), 6.35(m, 0.5H), chloro-phenyl)-pyrrolidin-1- 5.63(m,0.5H), 5.55(m, 1H), 5.30(m, 1H), 4.37(m, yl]-methanone 0.5H),3.95-4.09(m, 1H), 3.79-3.92(m, 1.5H), 3.01(m, 2H), 2.90(m, 1.5H),2.48(m, 1.5H), 1.86-2.03(m, 5H), 1.79(m, 0.5H), 1.45-1.60(m, 1.5H). 484(R)-[1-(3,5-Bis- MS(ES) 629.5(M+1)⁺. ¹H NMR(400MHz, CDCl₃,trifluoromethyl-benzyl)-5-(4- mixture of amide rotamers): δ 7.85(s, 2H),7.67(s, isopropyl-piperazin-1-yl)- 1H), 7.35(m, 0.5H), 7.21(m, 0.5H),7.12-7.18(m, 1H-[1,2,3]triazol-4-yl]-[2-(2- 1.5H), 6.96(m, 1.5H),6.28(d, 0.5H, J=7.4, 3.1), chloro-phenyl)-pyrrolidin-1- 5.65(d, 0.5H,J=7.4, 3.1), 5.52(s, 1H), 5.30(m, yl]-methanone 1H), 4.35(m, 0.5H),3.85-4.00(m, 1.5H), 2.93(m, 3H), 2.68(m, 2H), 2.50(m, 4.5H),1.91-2.00(m, 3.5H), 1.00(m, 6H). 485 [1-(3,5-Bis-trifluoromethyl- MS(ES)615.5(M+1)⁺. ¹H NMR(400MHz, CDCl₃, benzyl)-5-(3,5-dimethyl- mixture ofamide rotamers) δ 7.86(s, 1.5H), 7.81(s, piperazin-1-yl)-1H- 0.5H),7.68(s, 1H), 7.34(m, 0.5H), 7.12(m, 2.5H), [1,2,3]triazol-4-yl]-[2-(2-6.96(m, 1H), 6.26(d, 0.5H, J=7.0, 2.9), 5.62(d,chloro-phenyl)-pyrrolidin-1- 0.5H, J=7.0, 2.9), 5.51(s, 1H), 5.34(s,1H), yl]-methanone 4.28(m, 0.5H), 4.08(m, 0.5H), 3.96(m, 0.5H), 3.88(m,0.5H), 2.65-2.93(m, 4.5H), 2.47(m, 2.5H), 1.97(m, 3H), 0.92-1.00(m, 6H).486 [1-(3,5-Bis-trifluoromethyl- MS(ES) 616.5(M+1)⁺. ¹H NMR(400MHz,CDCl₃, benzyl)-5-(2,6-dimethyl- mixture of amide rotamers) δ 7.86(s,1.5H), 7.81(s, morpholin-4-yl)-1H- 0.5H), 7.68(s, 1H), 7.34(m, 0.5H),7.12(m, 2H), [1,2,3]triazol-4-yl]-[2-(2- 6.96(m, 1.5H), 6.26(d, 0.5H,J=7.5, 2.9Hz), chloro-phenyl)-pyrrolidin-1- 5.62(d, 0.5H, J=7.0, 2.9Hz),5.51(s, 1H), 5.34(s, 1H), yl]-methanone 4.31(m, 0.5H), 3.96-4.11(m, 1H),3.88(m, 0.5H), 3.47-3.70(m, 2H), 2.95-3.10(m, 2H), 2.34-2.50(m, 2.5H),1.88-2.01(m, 3.5H), 1.02-1.20(m, 6H).

EXAMPLE 487(R)-1-(4-{3-(3,5-Bis-trifluoromethyl-benzyl)-5-[2-(2-chloro-phenyl)-pyrrolidine-1-carbonyl]-3H-[1,2,3]triazol-4-yl}-piperazin-1-yl)-ethanone

Add acetyl chloride (20.0 mg, 0.26 mmol) to a solution of(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-piperazin-1-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.10 g, 0.17 mmol) and triethylamine (50.0 μL, 0.35 mmol) indichloromethane (3.0 mL). Stir at RT for 4 h, then dilute with water andextract with EtOAc. Wash the EtOAc extract with water and brine, thendry and concentrate. Purify the residue by flash chromatography using alinear gradient of 1 to 4% MeOH in dichloromethane to give the titlecompound (0.10 g, 95%). MS(ES) 629.4 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1mixture of amide rotamers) δ 7.87 (s, 0.5H), 7.82 (s, 1.5H), 7.64 (s,1H), 7.34 (s, 0.5H), 7.14-7.19 (m, 2H), 6.93-7.00 (m, 1.5H), 6.35 (m,0.5H), 5.61 (m, 0.5H), 5.57 (m, 1H), 5.39 (m, 1H), 4.38 (m, 0.5H),3.96-4.12 (m, 1H), 3.87 (m, 0.5H), 3.58-3.75 (m, 1.5H), 3.42 (m, 2H),2.87-3.00 (m, 4H), 2.62 (m, 0.5H), 2.42-2.51 (m, 1H), 2.08 (s, 1.5H),2.03 (s, 1.5H), 1.87-2.00 (m, 3H).

Using an analogous procedure to(R)-1-(4-{3-(3,5-Bis-trifluoromethyl-benzyl)-5-[2-(2-chloro-phenyl)-pyrrolidine-1-carbonyl]-3H-[1,2,3)triazol-4-yl}-piperazin-1-yl)-ethanonedescribed above, with the appropriate starting materials, the followingcompounds may be prepared. Ex. # Product Data 488 (R)-[1-(3,5-Bis-MS(ES) 665.4(M+1)⁺. ¹H NMR(400MHz, CDCl₃, trifluoromethyl-benzyl)-5-(4-mixture of amide rotamers) δ 7.87(s, 0.5H), 7.83(s,methanesulfonyl-piperazin-1- 0.5H), 7.81(s, 1H), 7.62(s, 1H), 7.35(m,0.5H), yl)-1H[1,2,3]triazol-4-yl]-[2- 7.16(m, 2H), 6.95-7.00(m, 1.5H),6.33(m, 0.5H), (2-chloro-phenyl)-pyrrolidin- 5.63(m, 0.5H), 5.55(m, 1H),5.37(m, 1H), 4.40(m, 1-yl]-methanone 0.5H), 3.96-4.10(m, 1H), 3.87(m,0.5H), 3.13-3.27(m, 4H), 2.98-3.06(m, 3H), 2.87(m, 1H), 2.81(s, 1.5H),2.77(s, 1.5H), 2.46(m, 1H), 1.88-2.03(m, 3H). 489 (R)-N-{3-(3,5-Bis-MS(ES) 674.4(M+1)⁺. ¹H NMR(400MHz, CDCl₃, trifluoromethyl-benzyl)-5-[2-mixture of amide rotamers) δ 7.90(s, 0.5H), 7.84(s, (2-chloro-phenyl)-2H), 7.58(s, 0.5H), 7.34(m, 0.5H), 7.17(m, 2.5H),pyrrolidine-1-carbonyl]-3H- 7.11(m, 0.5H), 7.02(m, 0.5H), 6.42(m, 0.5H),[1,2,3]triazol-4-yl}- 5.72(m, 1H), 5.61(m, 1H), 4.10-4.27(m, 1H),4.04(m, dimethanesulfonamide 0.5H), 3.88(m, 0.5H), 3.48(s, 1.5H),3.31(s, 1.5H), 3.27(s, 1.5H), 3.24(s, 1.5H), 2.45(m, 1H), 1.92-2.04(m,3H).

EXAMPLE 490(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxo-114-thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Add 30% aqueous hydrogen peroxide (2.0 mL, excess) to a solution of(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.08 g, 0.13 mmol) in MeOH (2.0 mL) and stir at RT. After 24 h, addwater and extract with EtOAc, then dry (Na₂SO₄), filter, andconcentrate. Purify the residue by flash chromatography using a lineargradient of 5 to 7% MeOH in dichloromethane to give the title compound(0.06 g, 75%). MS(ES) 620.3 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃, mixture ofamide rotamers) δ 7.88 (s, 0.5H), 7.84 (s, 0.5H), 7.82 (s, 1H), 7.63 (s,1H), 7.34 (m, 0.5H), 7.12-7.20 (m, 2H), 6.98 (m, 1.5H), 6.35 (m, 0.5H),5.63 (m, 0.5H), 5.56 (m, 1H), 5.38 (m, 1H), 4.43 (m, 0.5H), 3.96-4.08(m, 1H), 3.87 (m, 0.5H), 3.44 (m, 2H), 3.28 (m, 1H), 2.92-3.11 (m, 3H),2.81 (m, 2H), 2.40-2.51 (m, 1H), 1.87-2.02 (m, 3H).

EXAMPLE 491 (R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Add 30% aqueous hydrogen peroxide (5.0 mL, excess) to a solution of(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-thiomorpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.06 g, 0.10 mmol) in MeOH (2.0 mL) and stir at 80° C. for 18 h. Addwater and extract with EtOAc, then dry (Na₂SO₄), filter, andconcentrate. Purify the residue by flash chromatography using a lineargradient of 3 to 4% MeOH in dichloromethane to give the title compound(0.06 g, 95%) as a white solid. MS(ES) 636.0 (M+1)⁺. ¹H NMR (400 MHz,CDCl₃, 1:1 mixture of amide rotamers) δ 7.91 (s, 0.5H), 7.86 (s, 0.5H),7.79 (s, 1H), 7.60 (s, 1H), 7.34 (m, 0.5H), 7.16-7.23 (m, 2H), 6.97-7.04(m, 1.5H), 6.37 (m, 0.5H), 5.66 (m, 0.5H), 5.56 (m, 1H), 5.40 (m, 1H),4.47 (m, 0.5H), 4.06 (m, 1H), 3.90 (m, 0.5H), 3.48 (m, 2H), 3.30-3.42(m, 2H), 3.04 (m, 4H), 2.41-2.54 (m, 1H), 1.88-2.03 (m, 3H).

EXAMPLE 492(R)-1-{3-(3,5-Bis-trifluoromethyl-benzyl)-5-[2-(2-chloro-phenyl)-pyrrolidine-1-carbonyl]-3H-[1,2,3]triazol-4-yl}-piperidin-4-one

Add Dess-Martin periodinane (0.15 g, 0.35 mmol) to a solution of(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-hydroxy-piperidin-1-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.14 g, 0.23 mmol) in dichloromethane (3.0 mL) at 0° C. Stir themixture at 0° C. for 30 min, then warm to RT for 3 h. Dilute with waterand extract with EtOAc. Wash the organic layer with 1N NaOH, water, andbrine, then dry (Na₂SO4), and concentrate. Purify the residue by flashchromatography using a linear gradient of 30 to 45% EtOAc in hexanes togive the title compound (0.13 g, 93%). MS(ES) 600.3 (M+1)⁺. ¹H NMR (400MHz, CDCl₃, 1:1 mixture of amide rotamers) δ 7.88 (s, 0.5H), 7.84 (s,1.5H), 7.66 (s, 1H), 7.34 (m, 0.5H), 7.19 (m, 0.5H), 7.15 (m, 1.5H),6.94-7.01 (m, 1.5H), 6.38 (m, 0.5H), 5.62 (m, 1.5H), 5.45 (m, 1H), 4.41(m, 0.5H), 4.07 (m, 0.5H), 3.97 (m, 0.5H), 3.87 (m, 0.5H), 3.27 (m, 3H),3.09 (m, 1H), 2.46 (m, 5H), 1.98 (m, 3H).

EXAMPLE 493(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(3,6-dihydro-2H-pyridin-1-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-:1-yl]-methanone

Add DAST (45.0 μL, 0.36 mmol) to a solution of(R)-[1-(3,5-bis-trifluoromethyl-benzyl)-5-(4-hydroxy-piperidin-1-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone(0.11 g, 0.18 mmol) in dichloromethane (4.0 mL) at −78° C. Stir themixture at −78° C. for 30 min, then warm to RT for 1 h. Dilute withdichloromethane and wash with water and brine, then dry, andconcentrate. Purify the residue by flash chromatography using a lineargradient of 10 to 25% EtOAc in hexanes to give the title compound (0.03g, 28%). MS(ES) 584.3 (M+1)⁺. ¹H NMR (400 MHz, CDCl₃, 1:1 mixture ofamide rotamers) δ 7.85 (s, 1.5H), 7.80 (s, 0.5H), 7.67 (s, 1H),7.13-7.19 (m, 2H), 6.98 (m, 1.5H), 6.35 (m, 0.5H), 5.78 (m, 1H), 5.51(m, 1H), 5.33 (m, 1H), 4.39 (m, 0.5H), 4.08 (m, 0.5H), 3.97 (m, 0.5H),3.88 (m, 0.5H), 3.42 (m, 1H), 3.30 (m, 1H), 3.00-3.11 (m, 1.5H), 2.82(m, 0.5H), 2.47 (m, 1H), 2.11 (m, 2H), 1.88-2.04 (m, 3H).

EXAMPLE 494(R)-[5-Amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazol4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Combine EDCI (0.83 g, 0.44 mmol) with a solution of5-amino-1-(3,5-bis-trifluoromethyl-benzyl)-1H-[1,2,3]triazole-4-carboxylicacid (0.11 g, 0.31 mmol), (R)-2-(2-chloro-phenyl)-pyrrolidine (0.08 g,0.44 mmol), and DMAP (0.05 g, 0.44 mmol) in DMF (5.0 mL). After 48 h,treat the reaction mixture with saturated NaHCO₃ and extract with EtOAc.Wash the organic layer with 0.1N HCl, water, and brine, then dry andconcentrate to give the title compound (0.12 g, 75%) as a 1:1 mixture ofrotamers. MS(ES) 518 (M+1)⁺; ¹H NMR (400 MHz, DMSO-d₆ run at 100° C.) δ7.95 (s, 1H), 7.90 (s, 2H), 7.38 (m, 1H), 7.22 (m, 1H), 7.19 (m, 1H),7.14 (m, 1H), 6.40 (br s, 2H), 5.81 (br m, 1H), 5.58 (s, 2H), 4.20 (m,1H), 4.14 (m, 1H), 2.41 (m, 1H), 2.02-1.86 (m, 2H), 1.81 (m, 1H).

EXAMPLE 4951-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbothioicacid (2-fluoro-benzyl)-methyl-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-fluoro-benzyl)-methyl-amide (1 eq., 0.071 g, 0.13 mmol) andLawesson's reagent (0.55 eq., 0.029 g, 0.07 mmol) in toluene (3 mL,0.025 M). Stir at 80° C. until complete by TLC. Add H₂O and extract withCH₂Cl₂, dry over Na₂SO₄, and concentrate in vacuo. Purify bychromatography (0 to 50% EtOAc/Hexane gradient) on silica gel. R_(f)0.57 (50% EtOAc/ Hexane); MS(ES) 553.2 (M+1)⁺.

Using a similar procedure and the appropriate amide starting material,the following compounds may be prepared and isolated. Ex. # Product Data496 1-(3,5-Bis-trifluoromethyl-benzyl)- R_(f)=0.55(50% EtOAc/5-phenyl-1H-[1,2,3]triazole-4- Hexane); MS(ES) carbothioic acid(2-chloro- 569.2(M+1)⁺. benzyl)-methyl-amide 497[1-(3,5-Bis-trifluoromethyl-benzyl)- R_(f)=0.71(50% EtOAc/5-phenyl-1H-[1,2,3]triazol-4-yl]- Hexane); MS(ES)[2-(2-chloro-phenyl)-pyrrolidin- 595.3(M+1)⁺. 1-yl]-methanethione

EXAMPLE 4981-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid isopropyl-(2-trifluoromethoxy-benzyl)-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (0.15 g, 0.36 mmol) withisopropyl-(2-trifluoromethoxy-benzyl)-amine(0.084 g, 0.36 mmol), EDCI(0.069 g, 0.36 mmol), HOAt (0.049 g, 0.36 mmol), andN,N-diisopropylethylamine (0.10 ml) in DMF (5 mL) and stir at RT untilcomplete. Concentrate the mixture in vacuo, then dissolve the residue inEtOAc and wash with water and brine. Dry over Na₂SO₄, filter, andconcentrate. Purify by chromatography on silica gel to provide the titlecompound. MS (ES) 632.2 (M+1)⁺. Rf=0.47 (6.7% MeOH/CH₂Cl₂).

Using a procedure similar to that used for1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid isopropyl-(2-trifluoromethoxy-benzyl)-amide above, with theappropriate starting materials, the following compounds may be preparedand isolated. Ex. # Product Data 4991-(3,5-dichloro-benzyl)-5-pyridin-4yl-1H- MS(ES) 514.1(M+1)⁺,[1,2,3]triazole-4-carboxylic acid (2-chloro- 516.1(M+3)⁺. Rf=0.55(6.7%benzyl)-isopropyl-amide MeOH/CH₂Cl₂). 500[1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 547.2(M+1)⁺,pyridin-4-yl-1H-[1,2,3]triazol-4-yl]- 548.3(M+3)⁺. Anal. Calc'dC₂₆H₂₀F₆N₆O: (2-pyridin-4-yl-pyrrolidin-1-yl)-methanone C, 57.15; H,3.69; N, 15.38. Found: C, 56.19; H, 3.88; N, 14.61. 501[1-(3,5-Bis-trifluoromethyl-benzyl)-5- MS(ES) 594.1(M+1)⁺.pyridin-4-yl-1H-[1,2,3]triazol-4-yl]- Rf=0.26(6.7% MeOH/CH₂Cl₂).[2-(2-chloro-phenyl)-2-methyl-pyrrolidin-1- yl]-methanone

EXAMPLE 502 1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-phenyl)-isopropyl-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (0.27 g, 0.65 mmol) with oxalyl chloride (0.17 mL, 1.95 mmol) andDMF (1 drop, catalytic) in CH₂Cl₂ (5 mL) and stir at RT until acidchloride formation is complete. Concentrate the mixture in vacuo,redissolve in Et₂O and concentrate again. Dissolve the residue inpyridine (5 mL) and add (2-chloro-phenyl)-isopropyl-amine(0.11 g, 0.65mmol ) and DMAP (0.003 g, cat.) and heat until the reaction is complete.Then, quench with aqueous NaHCO₃ and extract with EtOAc twice. Dry thecombined organic extracts over Na₂SO₄, filter, and concentrate. Purifythe residue by chromatography on silica gel to provide the titlecompound. MS(ES) 568.1 (M+1)⁺.

Using a similar method and the appropriate starting materials, thefollowing compounds may be prepared and isolated. Ex. # Product Data 5031-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES) 568.1(M+1)⁺.1H-[1,2,3]triazole-4-carboxylic acid (2-chloro- phenyl)-isopropyl-amide504 1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES)622.1(M+1)⁺. 1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-Rf=0.57(6.7% MeOH/CH₂Cl₂). benzyl)-(2,2,2-trifluoro-ethyl)-amide 5051-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl- MS(ES)622.1058(M+1)⁺. 1H-[1,2,3]triazole-4-carboxylic acid (2-chloro-Rf=0.73(6.7% MeOH/CH₂Cl₂). benzyl)-(2,2,2-trifluoro-ethyl)-amide 5061-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-4-yl- MS(ES) 590.1(M+1)⁺;1H-[1,2,3]triazole-4-carboxylic acid isopropyl-(2- Rf=0.39(6.7%MeOH/CH₂Cl₂). trifluoromethoxy-benzyl)-amide 507[1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3- MS(ES) 594.1(M+1)⁺;yl-1H-[1,2,3]triazol-4-yl]- Rf=0.29(6.7% MeOH/CH₂Cl₂).[2-(2-chloro-phenyl)-2-methyl-pyrrolidin-1-yl]- methanone

EXAMPLE 5081-(3,5-Bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-isopropyl-amide

Combine1-(3,5-Bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-phenyl)-isopropyl-amide (0.11 g, 0.21 mmol) with anexcess of morpholine and heat the mixture near 50° C. for 3-5 hours, andthen allow to stir overnight at RT. Quench the mixture with aqueousNaHCO₃ and extract with EtOAc. Wash the combined organic extracts withwater, dry over Na₂SO₄, filter and concentrate. Purify by chromatographyon silica gel to provide the title compound. MS(ES) 576.1 (M+1)⁺;Rf=0.43 (6.25% MeOH/CH₂Cl₂).

EXAMPLE 5091-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid (2,6-dichloro-benzyl)-methyl-amide

To a solution of1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-imidazole-4-carboxylicacid (0.030 g, 0.072 mmol) in CH₂Cl₂ (0.7 mL) add HOBt-H₂O (0.020 g,0.145 mmol), 2,6-dichloro-n-methyl benzyl amine (0.028 g, 0.145 mmol),NEt₃ (0.050 mL, 0.362 mmol) and EDCI (0.028 g, 0.145 mmol) and stir theresulting orange mixture at RT. After 16 h., pour the mixture intoCH₂Cl₂, wash with saturated aqueous NaHCO₃ and extract the aqueous layerwith CH₂Cl₂ twice. Dry the combined organics over MgSO₄, filter,concentrate. Purify the residue by chromatography over silica gel usinga hexanes/EtOAc gradient to yield the title compound (0.030 g, 71%) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) 7.79 (s, 1H), 7.15-7.45 (m, 11H),5.19-5.30 (m, 2H), 5.05 (s,2H), 2.89 (s, 1.5H), 2.78 (s, 1.5H).

Using a method similar to the above Example, with the appropriatestarting materials, the following compounds may be prepared andisolated. Ex. # Product Data 5101-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl- ¹H NMR(400MHz, CDCl₃)1H-imidazole-4-carboxylic acid (2-chloro- 7.68(bd, J=12Hz, 1H), 7.59(s,0.5H), benzyl)-methyl-amide 7.27(s, 0.5H), 7.01-7.33(m, 11H), 5.11(s,1H), 5.01(s, 1H), 4.92(s, 1H), 4.68(s, 1H), 2.97(s, 1.5H), 2.81(s,1.5H). 511 1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl- R_(f)=0.13(100%EtOAc); 1H-imidazole-4-carboxylic acid cyclohexyl- MS(ES) 510.2(M+1)methyl-amide 512 1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-R_(f)=0.11(100% EtOAc) 1H-imidazole-4-carboxylic acid cyclopentyl-MS(ES) 496.2(M+1) methyl-amide 5131-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl- R_(f)=0.27(100% EtOAc)1H-imidazole-4-carboxylic acid (2-fluoro- MS(ES) 526.2(M+1)benzyl)-methyl-amide 514 1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl- ¹HNMR(400MHz) δ 1H-imidazole-4-carboxylic acid (2- 7.84-7.77(m, 2H),7.70-7.55(m, 2H), trifluoromethyl-benzyl)-methyl-amide 7.47-7.15(m, 9H),5.24(s, 1H), 5.14(s, 2H), 4.89(s, 2H), 3.07(s, 1.5H), 2.94(s, 1.5H).

EXAMPLE 515[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone

Dissolve1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2.13 g, 18.2 mmol), (±)-2-(2-chloro-phenyl)-pyrrolidine (0.93 g,5.12 mmol), and HOBt (0.86 g, 6.4 mmol) in a mixture of CH₂Cl₂ (50 mL)and triethylamine (2.14 mL, 15.4 mmol). Add EDCI (1.23 g, 6.4 mmol) andstir the solution at RT. After 24 h, dilute with CH₂Cl₂ (50 mL) and washwith 1 N HCl (100 mL), H₂O (100 mL), and saturated NaHCO₃ (100 mL). Drythe organic layer over MgSO₄, filter, and concentrate to give a paleyellow foam. Crystallize from EtOAc/hexanes (˜1:10) to provide 2.20 g(74%) of the title compound in two crops. The racemic mixture may beseparated using using chiral chromatography (SS Whelk-01, 20% 3Aalcohol/10% IPA/70% heptane) to give the (R)-enantiomer (earliereluting) and the (S)-enantiomer (later eluting). MS(ES) 579.1 (M+1)⁺;R_(f)=0.18 (2:1 hexanes/EtOAc).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition, that is, combined withpharmaceutically acceptable carriers, or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts, forpurposes of stability, convenience of crystallization, increasedsolubility, and the like.

Thus, the present invention provides pharmaceutical compositionscomprising a compound of the Formula I and a pharmaceutically acceptablediluent.

The compounds of Formula I can be administered by a variety of routes.In effecting treatment of a patient afflicted with disorders describedherein, a compound of Formula I can be administered in any form or modethat makes the compound bioavailable in an effective amount, includingoral and parenteral routes. For example, compounds of Formula I can beadministered orally, by inhalation, or by the subcutaneous,intramuscular, intravenous, transdermal, intranasal, rectal, occular,topical, sublingual, buccal, or other routes. Oral administration isgenerally preferred for treatment of the neurological and psychiatricdisorders described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances. (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)).

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material that can serve as a vehicle or medium forthe active ingredient. Suitable carriers or excipients are well known inthe art. The pharmaceutical composition may be adapted for oral,inhalation, parenteral, or topical use and may be administered to thepatient in the form of tablets, capsules, aerosols, inhalants,suppositories, solutions, suspensions, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or capsules or compressed into tablets.For the purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of the compound ofthe present invention, the active ingredient, but may be varieddepending upon the particular form and may conveniently be between 4% toabout 70% of the weight of the unit. The amount of the compound presentin compositions is such that a suitable dosage will be obtained.Preferred compositions and preparations according to the presentinvention may be determined by a person skilled in the art.

The tablets, pills, capsules, troches, and the like may also contain oneor more of the following adjuvants: binders such as povidone,hydroxypropyl cellulose, microcrystalline cellulose, gum tragacanth orgelatin; excipients such as dicalcium phosphate, starch, or lactose;disintegrating agents such as alginic acid, Primogel, corn starch andthe like; lubricants such as talc, magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents, suchas sucrose, aspartame, or saccharin, or a flavoring agent, such aspeppermint, methyl salicylate or orange flavoring, may be added. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier such as polyethyleneglycol or a fatty oil. Other dosage unit forms may contain other variousmaterials that modify the physical form of the dosage unit, for example,coatings. Thus, tablets or pills may be coated with sugar, shellac, orother coating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations typically contain at least 0.001% of acompound of the invention, but may be varied to be between 0.001 andabout 90% of the weight thereof. The amount of the compound of Formula Ipresent in such compositions is such that a suitable dosage will beobtained. The solutions or suspensions may also include one or more ofthe following adjuvants: sterile diluents, such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents, such as benzylalcohol or methyl paraben; antioxidants, such as ascorbic acid or sodiumbisulfite; chelating agents, such as ethylene diaminetetraacetic acid;buffers, such as acetates, citrates or phosphates; and agents for theadjustment of tonicity, such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Preferred compositionsand preparations are able to be determined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so, the carrier may suitably comprise asolution, ointment, or gel base. The base, for example, may comprise oneor more of the following: petrolatum, lanolin, polyethylene glycols,bees wax, mineral oil, diluents such as water and alcohol, andemulsifiers, and stabilizers. Topical formulations may contain aconcentration of a compound of Formula I or its pharmaceutical salt fromabout 0.1 to about 10% w/v (weight per unit volume).

The compounds of Formula I are antagonists of NK-1 receptors.Furthermore, the compounds of Formula I selectively antagonize NK-1receptors relative to other tachykinin receptors. The antagonistactivity of NK-1 receptor antagonists may be determined by the methodsbelow.

NK-1 Receptor Binding Assay

The IM-9 cell line is a well-characterized and readily available humancell line. See, e.g., Annals of the New York Academy of Science, 190:221-234 (1972); Nature (London), 251:443-444 (1974); Proceedings of theNational Academy of Sciences (USA), 71:84-88 (1974). These cells areroutinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamicinsulfate and 10% fetal calf serum.

The IM-9 cells are homogenized from cell pellets for crude membranes.The membranes are isolated by homogenizing tissue samples in 30 ml w/vwith 50 mM Tris buffer (pH 7.4). After an initial spin at 900×g, thesupernatant is transferred to a clean centrifuge tube and the membranesisolated by centrifugation at 38,000×g.

Approximately 25 μg of membranes are incubated with 0.2 nM[¹²⁵I]-substance P (NEN, Boston, Mass.) in a receptor binding assay. Theassay buffer contains 50 mM Tris, 3 mM MnCl₂, 0.02% bovine serumalbumin, 40 μg/ml bacitracin, 2 μg/ml chymostatin, 4 μg/ml leupeptin and40 μg/ml thiorphan (pH 7.4). Binding studies are conducted in a finalvolume of 200 μl containing various concentrations of test compounds.Non-specific binding is determined by incubating some tubes in thepresence of 1 μM substance P (Peninsula, Belmont, Calif.).

Binding is terminated 1 hour later by rapid filtration using a TOMTEC96-well cell harvester (TOMTEC, Orange, Conn.) through GF/A filters thathave been presoaked with 0.3% polyethyleneimine (Sigma, St Louis) for 1hour. The filters are washed with 5 ml of ice-cold 50 mM Tris buffer (pH7.4) and placed in a drying oven at 60° C. The dried filters are treatedwith MeltiLex A melt-on scintillator sheets (Wallac, Gaithersburg, Md.),and the radioactivity retained on the filters counted using the Wallac1205 Betaplate scintillation counter. The results are analyzed using aLog-Logit plot from a Microsoft Excel™ workbook and converted to Kivalues with the Cheng-Prusoff equation. Protein concentrations aremeasured using Coomassie® protein assay reagent (Pierce, Rockford,Ill.), with BSA for standards (Bradford, 1976).

Binding studies are carried out to evaluate the ability of compounds ofthe present invention to inhibit NK-1 receptor activation. Such studiesprovide in vitro data regarding the efficacy of the compounds of thepresent invention. Representative Examples of the compounds of Formula(I) were tested in the receptor binding assay described herein and weredemonstrated to have binding affinities (K_(i) values) of ≦100 nM.

Several preclinical laboratory animal models have been described for anumber of the disorders associated with an excess of tachykinins. Onesuch in vivo assay, described below, may be used to determine whetherNK-1 receptor antagonists are CNS-penetrant.

Gerbil Foot-Tapping

The gerbil foot-tapping assay is well recognized in the art. Forexample, see Rupniak et al., Eur. J Pharmacol. (1997) 326: 201-209.

Male Gerbils (Mongolian), weighing between 20-40 gm (Harlan Labs,Indianapolis, Ind.) are used for the experiments. Animals are allowed toacclimate prior to any testing.

An NK-1 receptor agonist, such as GR73632 (δ-Aminovaleryl [Pro⁹,N—Me-Leu¹⁰]-Substance P(7-11)) (Peninsula Labs), is dissolved inacidified saline (1 ml acetic acid in 1 liter of 0.09% saline) to make a1 mg/ml solution (corrected for peptide content). The stock solution isfurther diluted to 10 μg/ml in saline (0.9% normal saline), aliquotedand kept frozen until use. The stock solution is further diluted to 3pmol/5 μl in saline for i.c.v. injections.

Test compounds are formulated in appropriate vehicle to a concentrationof 1 ml/100 gm body weight. Compounds are dosed by oral gavage (p.o.) orsubcutaneously (s.c.) or intraperitoneally (i.p.) at pre-determinedtimes prior to intracerebroventricular (i.c.v.) challenge of agonist.For i.c.v. administration, test compound is co-injected with agonist.

Free hand i.c.v. injection is performed by direct vertical insertion ofa cuffed 27-gauge needle with a Hamilton 50 μl syringe, to a depth of4.5 mm below bregma. Light anesthesia with isoflurane may be neededprior to the injection, but is not used routinely.

Following i.c.v. injection of agonist, animals are placed in a plexiglasobservation box, and hind foot tapping events are counted for 5 minutes.Data collection is computerized.

Data are analyzed by ANOVA followed by Dunnett's test using JMPstatistical program (IBM platform). Data are expressed as number ofevents/5 minutes.

The results of NK-1 receptor binding studies demonstrate the ability ofcompounds of the present invention to act as antagonists of NK-1receptors. It is recognized that the compounds of the present inventionwould be expected to inhibit the effects of NK-1 receptor activation.Thus, the compounds of the present invention are expected to be usefulin the treatment of various disorders associated with excesstachykinins, as described to be treated herein, and other disorders thatcan be treated by such antagonists, as are appreciated by those skilledin the art.

In one embodiment, the present invention provides methods of treatingdisorders selected from the group consisting of anxiety, depression,psychosis, schizophrenia and other psychotic disorders,neurodegenerative disorders (including senile dementia of theAlzheimer's type, Alzheimer's disease, AIDS-associated dementia, andDown's syndrome), seizure disorders (including generalized and partialseizures), demyelinating diseases (including multiple sclerosis andamyotrophic lateral sclerosis), neuropathological disorders (includingperipheral neuropathy, diabetic and chemotherapy-induced neuropathy, andpost-herpetic and other neuralgias), acute and chronic obstructiveairway diseases (including adult respiratory distress syndrome,bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, andasthma), inflammatory diseases (including inflammatory bowel disease,psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis),disorders of the musculo-skeletal system (such as osteoporosis),allergies (including eczema and rhinitis), hypersensitivity disorders(such as poison ivy), ophthalmic diseases (such as conjunctivitis,vernal conjunctivitis, and the like), cutaneous diseases (includingcontact dermatitis), atopic dermatitis, urticaria, other eczematoiddermatites, addiction disorders (including alcoholism), stress-relatedsomatic disorders, reflex sympathetic dystrophy (such as shoulder/handsyndrome), dysthymic disorders, adverse immunological reactions (such asrejection of transplanted tissues), disorders related to immuneenhancement or suppression (such as systemic lupus erythematosis),gastrointestinal disorders, diseases associated with the neuronalcontrol of viscera (such as ulcerative colitis, Crohn's disease andirritable bowel syndrome); disorders of bladder function (such asbladder detrusor hyper-reflexia and incontinence), atherosclerosis,fibrosis and collagen diseases (such as scleroderma and eosinophilicfascioliasis), irritative symptoms of benign prostatic hypertrophy,disorders associated with blood pressure (such as hypertension),disorders of blood flow caused by vasodilation or vasospastic diseases(such as angina, migraine, and Reynaud's disease), emesis (includingchemotherapy-induced nausea and acute or delayed emesis), and pain ornociception (including that attributable to or associated with any ofthe foregoing conditions), comprising: administering to a patient inneed thereof an effective amount of a compound of Formula I or apharmaceutical composition thereof. That is, the present inventionprovides methods of treating disorders associated with an excess oftachykinins, comprising: administering to a patient in need thereof aneffective amount of a compound of Formula I or a pharmaceuticalcomposition thereof.

The present invention contemplates the various disorders described to betreated herein and others that can be treated by such antagonists, asappreciated by those skilled in the art.

The disorders associated with an excess of tachykinins are treated byadministering an effective amount of a compound or pharmaceuticalcomposition of Formula 1. An effective amount can be readily determinedby the attending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining an effective amount, the dose ofa compound of Formula I, a number of factors are considered by theattending diagnostician, including, but not limited to: the compound ofFormula I to be administered; the species of mammal—its size, age, andgeneral health; the specific disorder involved; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of other concomitant medication; and other relevantcircumstances.

An effective amount of a compound of Formula I is expected to vary fromabout 0.001 milligram per kilogram of body weight per day (mg/kg/day) toabout 100 mg/kg/day. Preferred amounts may be readily determined by oneskilled in the art.

Of the disorders associated with an excess of tachykinins that aretreated according to the present invention, the treatment of depression,anxiety, inflammatory bowel disease, irritable bowel syndrome, andemesis (chemotherapy-induced nausea and acute or delayed emesis) areparticularly preferred.

Thus, in a preferred embodiment, the present invention provides a methodfor treating a depressive disorder, including major depressive disorder,comprising: administering to a patient in need thereof an effectiveamount of a compound of Formula I or a pharmaceutical compositionthereof.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, including generalized anxiety disorder, panicdisorder, and obsessive-compulsive disorder, comprising: administeringto a patient in need thereof an effective amount of a compound ofFormula I or a pharmaceutical composition thereof.

Disorders of the central nervous system, including depressive andanxiety disorders, have been characterized in the Diagnostic andStatistical Manual of Mental Disorders (DSM-IV™) (1994, AmericanPsychiatric Association, Washington, D.C.). The DSM-IV™ provides cleardescriptions of diagnostic categories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for these disorders, and that these systems mayevolve with medical scientific progress. For instance, the ICHPPC-2(International Classification of Health Problems in Primary Care)(3^(rd) edition, 1983, Oxford University Press, Oxford) provides analternative classification system. Thus, the terms “depression,”“depressive disorders,” “anxiety,” and “anxiety disorders” are intendedto include like disorders that are described in other diagnosticsources.

According to the fourth edition of the DSM-IV™, major depressivedisorders are characterized by one or more major depressive episodes,which consist of a period of at least two weeks of depressed mood orloss of pleasure, in addition to other symptoms. Thus, the skilledartisan will recognize that the present invention is useful for thetreatment of either a single episode or recurrent episodes of majordepressive disorder.

The skilled artisan will appreciate that other depressive disorders mayalso be treated by administering an effective amount of a compound ofFormula (I). Such other depressive disorders include dysthymic disorder,and depressive disorders not otherwise specified (for example,premenstrual dysphoric disorder, minor depressive disorder, recurrentbrief depressive disorder, or postpsychotic depressive disorder ofschizophrenia). In addition, the treatment of depression by thecompounds of Formula (I) may also include the treatment of mooddisorders due to a general medical condition and substance-induced mooddisorders.

The DSM-IV™ also provides a diagnostic tool for anxiety and relateddisorders. These disorders include: panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, specificphobia, social phobia or social anxiety disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, substance-induced anxiety disorder and anxiety disorder nototherwise specified. As used herein, the term “anxiety” includestreatment of those anxiety disorders and related disorders described inthe DSM-IV.

1. A compound of Formula I:

wherein: D¹ is a C₁-C₃ alkane-diyl; D² is CH or nitrogen; D⁴ is oxygenor sulfur; R¹ is phenyl, which phenyl is optionally substituted with oneto three substitutents independently selected from the group consistingof halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, difluoromethyl,trifluoromethyl, and trifluoromethoxy; R² is selected from the groupconsisting of hydroxy, C₁-C₄ alkyl, optionally substituted phenyl,naphthyl, C₃-C₁₀ cycloalkyl, pyridyl, optionally substitutedpyrrolidinyl, optionally substituted piperidinyl, which C₁-C₄ alkyl isoptionally substituted with hydroxy, C₁-C₂ alkoxy, optionallysubstituted phenyl, pyridyl, —NR⁶R⁷, or naphthyl; which pyridyl isfurther optionally substituted with one to two halo, C₁-C₃ alkyl; R³ isC₁-C₄ alkyl, optionally substituted phenyl, —C(O)—R⁴, or —S(O)₂—R⁴,which C₁-C₄ alkyl is further optionally substituted with R⁴; R⁴ isoptionally substituted phenyl; or R² and R³, together with the nitrogento which they are attached, form a 4-11 membered heterocyclic ring,which heterocyclic ring is further optionally substituted with one tofour substituents independently selected from the group consisting ofoptionally substituted phenyl, C₃-C₆ cycloalkyl, pyridyl, halo, hydroxy,oxo, and C₁-C₄ alkyl; wherein the C₁-C₄ alkyl is further optionallysubstituted with one to two substituents selected from the groupconsisting of C₁-C₃ alkoxy, optionally substituted phenyl, oxo, phenoxy,pyridyl, and pyrrolidinyl; R⁶ and R⁷ are each independently hydrogen,C₁-C₄ alkyl, —S(O)₂—CH₃, or C₁-C₄ alkoxycarbonyl, or R⁶ and R⁷, togetherwith the nitrogen to which they are attached, form a 4-7 memberedsaturated heterocyclic ring; R⁵ is hydrogen, halo, trifluoromethyl,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, furyl, pyrazolyl,imidazolyl, —NR¹³R¹⁴, pyridyloxy, benzyloxy, phenyl, phenoxy, pyrrolyl,thienyl, phenylthio, or anilino, which phenyl, phenoxy, pyrrolyl,thienyl, phenylthio, or anilino group may be optionally substituted onthe ring with one to two substituents independently selected from thegroup consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl,and —S(O)_(q)(C₁-C₄ alkyl), or R⁵ is a radical selected from the groupconsisting of:

wherein W is a bond, —CHR¹⁵—, —C(O)—, —O—, —NR¹⁵—, or —S(O)_(q)—; q is0, 1, or 2; R¹⁵ is selected from the group consisting of hydrogen,hydroxy, C₁-C₄ alkyl, acetyl, carbamoyl, phenyl, benzyl, and —S(O)₂CH₃;Z¹, Z², and Z³ are each independently CH or nitrogen; R¹³ and R¹⁴ areeach independently hydrogen, C₁-C₄ alkyl, —S(O)₂—CH₃ or C₃-C₆cycloalkyl; wherein the C₁-C₄ alkyl is optionally substituted with oneC₁-C₂ alkoxy or di(C₁-C₂ alkyl)amino; or R¹³ and R¹⁴, together with thenitrogen to which they are attached, form a 4-7 membered saturatedheterocyclic ring; which 4-7 membered saturated heterocyclic ring isfurther optionally substituted with one to two C₁-C₂ alkyl; or apharmaceutically acceptable salt thereof; with the proviso that thefollowing compounds are not claimed:[5-methyl-1-(3-pyrrolidin-1-ylpropyl)-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;{1-[2-(4-nitrophenyl)ethyl]-5-methyl-1H-1,2,3-triazol-4-yl}piperazin-1-yl-methanone;[1-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;[5-methyl-1-(3-imidazol-1-ylpropyl)-1H-1,2,3-triazol-4-yl]piperazin-1-yl-methanone;(5-methyl-1-benzyl-1H-1,2,3-triazol-4-yl)piperazin-1-yl-methanone;(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-1,4-diazepan-1-yl-methanone;[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-morpholin-4-yl-methanone;1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-amino-ethyl)-(2-chloro-benzyl)-amide dihydrochloride;1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-amino-ethyl)-(2-chloro-benzyl)-amide hydrochloride;1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide dihydrochloride;1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridyl-4-yl-1H-[1,2,3]triazole-4-carboxylicacid (2-amino-ethyl)-[1-(2-chloro-phenyl)-ethyl]-amide dihydrochloride;{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl-(2-chloro-benzyl)-amino]-ethyl}-carbamicacid tert-butyl ester;{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl}-carbamicacid tert-butyl ester;(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamicacid tert-butyl ester;(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamicacid tert-butyl ester;{2-[[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-(2-chloro-benzyl)-amino]-ethyl}-carbamicacid tert-butyl ester; and(2-{[1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazole-4-carbonyl]-[1-(2-chloro-phenyl)-ethyl]-amino}-ethyl)-carbamicacid tert-butyl ester.
 2. The compound of claim 1 wherein D⁴ is oxygen.3. The compound of claim 2 wherein D² is nitrogen.
 4. The compound ofclaim 3 wherein D¹ is methylene.
 5. The compound of claim 4 wherein R¹is 3,5-bis-trifluoromethyl-phenyl.
 6. The compound of claim 5 wherein R⁵is phenyl.
 7. The compound of claim 6 wherein R² is C₁-C₄ alkyl, whichis optionally substituted with optionally substituted phenyl.
 8. Thecompound of claim 7 wherein R² is 2-chloro-benzyl.
 9. The compound ofclaim 8 wherein R³ is C₁-C₄ alkyl, which C₁-C₄ alkyl is optionallysubstituted with R⁴.
 10. The compound of claim 9 wherein R³ is methyl.11. The compound of claim 6 wherein R² and R³, together with thenitrogen to which they are attached, form a 4-11 membered heterocyclicring, which heterocyclic ring is further optionally substituted with oneto four substituents independently selected from the group consisting ofoptionally substituted phenyl, C₃-C₆ cycloalkyl, pyridyl, halo, hydroxy,oxo, and C₁-C₄ alkyl, wherein the C₁-C₄ alkyl is further optionallysubstituted with one to two substituents selected from the groupconsisting of C₁-C₃ alkoxy, optionally substituted phenyl, oxo, phenoxy,pyridyl, and pyrrolidinyl.
 12. The compound of claim 11 wherein R² andR³, together with the nitrogen to which they are attached, formpyrrolidin-1-yl, which pyrrolidin-1-yl is further optionally substitutedwith one to four substituents independently selected from the groupconsisting of optionally substituted phenyl, C₃-C₆ cycloalkyl, pyridyl,halo, hydroxy, oxo, and C₁-C₄ alkyl, wherein the C₁-C₄ alkyl is furtheroptionally substituted with one to two substituents selected from thegroup consisting of C₁-C₃ alkoxy, optionally substituted phenyl, oxo,phenoxy, pyridyl, and pyrrolidinyl.
 13. The compound of claim 12 whereinR² and R³, together with the nitrogen to which they are attached, form2-(2-chloro-phenyl)-pyrrolidin-1-yl.
 14. The compound of claim 1 whereinthe compound is1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylicacid (2-chloro-benzyl)-methyl-amide.
 15. The compound of claim 1 whereinthe compound is[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone.16. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier, excipient, or diluent.
 17. A methodfor treating a condition associated with an excess of tachykinins,comprising: administering to a patient in need thereof an effectiveamount of a compound of Formula (I):

wherein: D¹ is a C₁-C₃ alkane-diyl; D² is CH or nitrogen; D⁴ is oxygenor sulfur; R¹ is phenyl, which phenyl is optionally substituted with oneto three substitutents independently selected from the group consistingof halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, difluoromethyl,trifluoromethyl, and trifluoromethoxy; R² is selected from the groupconsisting of hydroxy, C₁-C₄ alkyl, optionally substituted phenyl,naphthyl, C₃-C₁₀ cycloalkyl, pyridyl, optionally substitutedpyrrolidinyl, optionally substituted piperidinyl, which C₁-C₄ alkyl isoptionally substituted with hydroxy, C₁-C₂ alkoxy, optionallysubstituted phenyl, pyridyl, —NR⁶R⁷, or naphthyl; which pyridyl isfurther optionally substituted with one to two halo, C₁-C₃ alkyl; R³ isC₁-C₄ alkyl, optionally substituted phenyl, —C(O)—R⁴; or —S(O)₂—R⁴,which C₁-C₄ alkyl is further optionally substituted with R⁴; R⁴isoptionally substituted phenyl; or R² and R³, together with the nitrogento which they are attached, form a 4-11 membered heterocyclic ring,which heterocyclic ring is further optionally substituted with one tofour substituents independently selected from the group consisting ofoptionally substituted phenyl, C₃-C₆ cycloalkyl, pyridyl, halo, hydroxy,oxo, and C₁-C₄ alkyl; wherein the C₁-C₄ alkyl is further optionallysubstituted with one to two substituents selected from the groupconsisting of C₁-C₃ alkoxy, optionally substituted phenyl, oxo, phenoxy,pyridyl, and pyrrolidinyl; R⁶ and R⁷ are each independently hydrogen,C₁-C₄ alkyl, —S(O)₂—CH₃, or C₁-C₄ alkoxycarbonyl, or R⁶ and R⁷, togetherwith the nitrogen to which they are attached, form a 4-7 memberedsaturated heterocyclic ring; R⁵ is hydrogen, halo, trifluoromethyl,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₃-C₆ cycloalkyl, furyl, pyrazolyl,imidazolyl, —NR¹³R¹⁴, pyridyloxy, benzyloxy, phenyl, phenoxy, pyrrolyl,thienyl, phenylthio, or anilino, which phenyl, phenoxy, pyrrolyl,thienyl, phenylthio, or anilino group may be optionally substituted onthe ring with one to two substituents independently selected from thegroup consisting of halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl,and —S(O)_(q)(C₁-C₄ alkyl), or R⁵ is a radical selected from the groupconsisting of:

wherein W is a bond, —CHR¹⁵—, —C(O)—, —O—, —NR¹⁵—, or —S(O)_(q)—; q is0, 1, or 2; R¹⁵ is selected from the group consisting of hydrogen,hydroxy, C₁-C₄ alkyl, acetyl, carbamoyl, phenyl, benzyl, and —S(O)₂CH₃;Z¹, Z², and Z³ are each independently CH or nitrogen; R¹³ and R¹⁴ areeach independently hydrogen, C₁-C₄ alkyl, —S(O)₂—CH₃ or C₃-C₆cycloalkyl; wherein the C₁-C₄ alkyl is optionally substituted with oneC₁-C₂ alkoxy or di(C₁-C₂ alkyl)amino; or R¹³ and R¹⁴, together with thenitrogen to which they are attached, form a 4-7 membered saturatedheterocyclic ring; which 4-7 membered saturated heterocyclic ring isfurther optionally substituted with one to two C₁-C₂ alkyl; or apharmaceutically acceptable salt thereof.
 18. The method of claim 17wherein the condition associated with an excess of tachykinins isselected from the group consisting of depression, anxiety, irritablebowel syndrome, and emesis. 19-20. (canceled)
 21. A compound selectedfrom the group consisting of:[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxy-pyridin-4-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)pyrrolidin-1-yl)-methanone,[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(1-oxy-pyridin-3-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone,and(R)-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-(3,6-dihydro-2H-pyridin-1-yl)-1H-[1,2,3]triazol-4-yl]-[2-(2-chloro-phenyl)-pyrrolidin-1-yl]-methanone.